CN110382490A - Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition - Google Patents
Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition Download PDFInfo
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to quinazoline compounds and preparation method thereof, purposes and pharmaceutical compositions.The quinazoline compounds are by shown in formula (I), it is phosphatidyl-inositol 3-kinase (PI3K) inhibitor, it can be used for preventing and/or treating disease relevant to PI3K activity, such as cancer, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease.
Description
The invention belongs to pharmaceutical technology field, it is related to a kind of quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition.
Phosphatidyl-inositol 3-kinase (phosphatidylinositol 3-kinase, PI3K) belongs to lipid kinase family, according to the difference of its structure, adjustment effect and lipid substrate specificity, can be divided into three categories (I, II and III).That research is the most deep at present is I class PI3K, and such PI3K is heterodimer, is made of an adjusting subunit (p85) and a catalytic subunit (p110).I class PI3K includes 4 hypotypes, wherein two hypotypes of PI3K α and PI3K β are widely present in various types of cells, and another two hypotype PI3K δ and PI3K γ are then mainly distributed in leucocyte (Vanhaesebroeck etc., Trends Biochem Sci., 2005,30 (4): 194-204).Major downstream effector as receptor tyrosine kinase (RTK) and g protein coupled receptor (GPCR), PI3K passes through catalysis phosphatidylinositols -4,5- diphosphonic acid (PIP2) generates phosphatidylinositols -3,4,5- triphosphoric acid (PIP3), thus by the signal transduction of various growth factors and cell factor to intracellular.PIP3 is then used as intracellular second messenger, serine/threonine protein kitase (protein kinase B can be activated, AKT) and the effector in downstream, including mammal rapamycin target point protein (mTOR), to regulate and control various kinds of cell function.
PI3K signal path is one of most common abnormal signal access in tumour cell, has critical influence to the generation of tumour, development process.The gene PIK3CA of p110 α is especially encoded in most of tumours, lung cancer, intestinal cancer, oophoroma, head-neck carcinoma, gastric cancer, prostate cancer, the cancer of the brain, liver cancer, tumor in digestive tract, occurs massive amplification and variation (Zhao etc. in leukaemia in such as breast cancer, Nat.Drug Discov.Rev.2009,8:627-644).In recent years, other interdependent nodes such as AKT and mTOR on PI3K and its access become the popular target of anti-tumor drugs targeting.The PI3K inhibitor of various structures framework types is reported successively, they all show superior antitumous effect in cell and animal model, and there are multiple compounds to carry out clinical test for solid tumor and neoplastic hematologic disorder in a manner of single medicine or administering drug combinations, such as BKM120 (Novartis, the clinical III phase), BEZ235 (Novartis, the clinical II phase), PF-05212384 (Pfizer, the clinical II phase), BAY 80-6946 (Bayer, the clinical III phase), XL147 (Exelixis, clinical I/II phase) etc..First PI3K inhibitor Idelalisib (Gilead in 2014, PI3K δ selective depressant) FDA approval is obtained, for treating chronic lymphocytic leukemia (CLL), recurrent follicular B cells non-Hodgkin lymphoma (FL) and recurrent small lymphocyte lymthoma (SLL).In addition to tumour, PI3K also has important adjustment effect to inflammation, immunity disease, cardiovascular disease, virus infection, metabolism/endocrine dysfunction or neurological disease, some compounds such as GSK2269557 (chronic obstructive pulmonary disease, the clinical II phase), GSK2126458 (idiopathic pulmonary fibrosis, clinical I phase), UCB-5857 (primary Sjogren's syndrome, the clinical II phase) and RV-1729 (chronic obstructive pulmonary disease, clinical I phase) etc. for these diseases entered clinical experimental stage.
The drug targets that PI3K has become to have a great attraction, but also need to research and develop safer and more effective PI3K inhibitor for prevent and/or treating cancer, immunological diseases, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of new PI3K inhibitor, preparation method, pharmaceutical composition and purposes, such PI3K inhibitor is to I class PI3K, including PI3K α, PI3K β, PI3K γ and/or PI3K δ, especially there is stronger inhibitory activity to PI3K α, to have preferably prevention and/or therapeutic effect to disorders such as cancers, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or the neurological disease mediated by PI3K.
To solve technical problem of the invention, the invention provides the following technical scheme:
There is provided a kind of formula (I) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salts for the first aspect of technical solution of the present invention:
Wherein
R
1For C
1-3Alkyl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；As the R
2When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
3Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
4Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
R
5Selected from hydrogen, amino, C
1-3Alkyl amino, C
1-3Alkyl-carbonyl-amino or cyclopropyl methylamino.
In a preferred embodiment, the present invention provides a kind of formula (II) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salts:
Wherein
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl, preferably C
1-3Alkyl；
R
1Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；As the R
1When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
2Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
3Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl replace: hydrogen, halogen, C wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In a further preferred embodiment, the present invention provides a kind of formula (II) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
L is selected from a singly-bound or C
1-3Alkylidene, wherein C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl, preferably C
1-3Alkyl；
R
1Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Optionally, R
1Replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
2Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
3Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl replace: hydrogen, halogen, C wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In another further preferred embodiment, the present invention provides a kind of formula (II) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl, preferably C
1-3Alkyl；
R
1For 3-7 member oxygen heterocycle alkyl, R
1Optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
2Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
3Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl replace: hydrogen, halogen, C wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In a further preferred embodiment, R
1It is selected from:
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino.
In a further preferred embodiment, R
1It is selected from:
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino.
In a further preferred embodiment, each Rb is independently selected from F, methyl or methoxy.
In another further preferred embodiment, the present invention provides a kind of formula (II) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
L is selected from singly-bound or-CH
2,
R
1Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Preferably, R
1Selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, R
1Selected from 3-7 membered heterocycloalkyl, further preferred 3-7 member oxygen heterocycle alkyl, including but not limited to
As the R
1When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；Preferably, each Rb is independently selected from F, methyl or methoxy；
R
2Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
3Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl replace: hydrogen, halogen, C wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In another further preferred embodiment, the present invention provides a kind of formula (II) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；Preferably, L is selected from singly-bound or-CH
2-；
Ra is selected from hydrogen, halogen or C
1-3Alkyl, preferably C
1-3Alkyl；
R
1Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Preferably, R
1Selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, R
1Selected from 3-7 membered heterocycloalkyl, further preferred 3-7 member oxygen heterocycle alkyl, including but not limited to
As the R
1When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；Preferably, each Rb is independently selected from F, methyl or methoxy；
R
2Selected from methoxyl group, chlorine or methyl；
R
3Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl replace: hydrogen, halogen, C wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In another further preferred embodiment, the present invention provides a kind of formula (II) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；Preferably, L is selected from singly-bound or-CH
2-；
Ra is selected from hydrogen, halogen or C
1-3Alkyl, preferably C
1-3Alkyl；
R
1Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Preferably, R
1Selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, R
1Selected from 3-7 membered heterocycloalkyl, further preferred 3-7 member oxygen heterocycle alkyl, including but not limited to
As the R
1When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；Preferably, each Rb is independently selected from F, methyl or methoxy；
R
2Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；Preferably, R
2Selected from methoxyl group, chlorine or methyl；
R
3Selected from C
1-3Alkyl, 3-7 member naphthenic base, phenyl or thienyl replace: hydrogen, halogen, C wherein the phenyl and thienyl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In a further preferred embodiment, R
3Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally independently selected by one or more from fluorine or the group of chlorine replaces.
Specifically, preferred compound is as follows according to the present invention:
In another preferred embodiment, the present invention provides a kind of formula (III) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salts:
Wherein
R
1Selected from C
1-3Alkyl, C
1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl or 5-6 unit's heteroaryl are optionally replaced by least one group selected from the following: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
Ring A is selected from 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In a further preferred embodiment, the present invention provides a kind of formula (III) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1Selected from C
1-3Alkyl, C
1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl or 5-6 unit's heteroaryl are optionally replaced by least one group selected from the following: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
Ring A is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In another further preferred embodiment, the present invention provides a kind of formula (III) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1Selected from C
1-3Alkyl, C
1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2Selected from hydrogen, C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl or 5-6 unit's heteroaryl are optionally replaced by least one group selected from the following: halogen, C
1-3Alkyl, amino, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
Ring A is 3-7 member oxygen heterocycle alkyl；
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In a further preferred embodiment, ring A is selected from:
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In a further preferred embodiment, each R
3Independently selected from methyl.
In another further preferred embodiment, the present invention provides a kind of formula (III) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1Selected from C
1-3Alkyl, C
1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from singly-bound or-CH
2-；
R
2Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl or 5-6 unit's heteroaryl are optionally replaced by least one group selected from the following: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
Ring A is selected from 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Preferably, ring A is selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, ring A be selected from 3-7 membered heterocycloalkyl, further preferred 3-7 member oxygen heterocycle alkyl, including but not limited to
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In another further preferred embodiment, the present invention provides a kind of formula (III) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1Selected from methyl, ethyl, Cvclopropvlmethvl or acetyl group；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；Preferably, L is selected from singly-bound or-CH
2-。
Ra is selected from hydrogen, halogen or C
1-3Alkyl；It is preferred that C
1-3Alkyl；
R
2Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl or 5-6 unit's heteroaryl are optionally replaced by least one group selected from the following: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
Ring A is selected from 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Preferably, ring A is selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, ring A be selected from 3-7 membered heterocycloalkyl, further preferred 3-7 member oxygen heterocycle alkyl, including but not limited to
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In another further preferred embodiment, the present invention provides a kind of formula (III) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1Selected from C
1-3Alkyl, C
1-3Alkyl-carbonyl or Cvclopropvlmethvl；Preferably, R
1Selected from methyl, ethyl, Cvclopropvlmethvl or acetyl group；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；Preferably, L is selected from singly-bound or-CH
2-。
Ra is selected from hydrogen, halogen or C
1-3Alkyl；It is preferred that C
1-3Alkyl；
R
2Selected from C
1-3Alkyl, 3-7 member naphthenic base, phenyl or thienyl replace: hydrogen, halogen, C wherein the phenyl and thienyl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy；
Ring A is selected from 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Preferably, ring A is selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, ring A be selected from 3-7 membered heterocycloalkyl, further preferred 3-7 member oxygen heterocycle alkyl, including but not limited to
Each R
3Independently selected from hydrogen, C
1-3Alkyl, halogen, cyano, trifluoromethyl, C
1-3The C that alkoxy, hydroxyl replace
1-3Alkyl, C
1-3Alkyl amine group or two (C
1-3Alkyl) amido；
M is 0,1,2,3 or 4.
In a further preferred embodiment, R
2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally independently selected by one or more from fluorine or the group of chlorine replaces.
Specifically, preferred compound is as follows according to the present invention:
In another preferred embodiment, the present invention provides a kind of formula (IV) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salts:
Wherein
R
1For C
1-3Alkyl, preferably methyl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；As the R
2When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
3Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
4Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In a further preferred embodiment, the present invention provides a kind of formula (IV) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1For C
1-3Alkyl, preferably methyl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；R
2Optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
3Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
4Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In another further preferred embodiment, the present invention provides a kind of formula (IV) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1For C
1-3Alkyl, preferably methyl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from hydrogen, halogen or C
1-3Alkyl；
R
2For 3-7 member oxygen heterocycle alkyl, R
2Optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；
R
3Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
4Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In a further preferred embodiment, R
2It is selected from:
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino.
In a further preferred embodiment, R
2It is selected from:
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino.
In a further preferred embodiment, Rb is independently selected from F or methyl.
In another further preferred embodiment, the present invention provides a kind of formula (IV) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1For C
1-3Alkyl, preferably methyl；
L is selected from singly-bound or-CH
2,
R
2Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；Preferably, R
2Selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, R
2For 3-7 membered heterocycloalkyl, preferably 3-7 member oxygen heterocycle alkyl, including but not limited to
It preferably includes, but is not limited to
As the R
2When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；Preferably, Rb is independently selected from F or methyl；
R
3Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；
R
4Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In another further preferred embodiment, the present invention provides a kind of formula (IV) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1For C
1-3Alkyl, preferably methyl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；Preferably, L is selected from singly-bound or-CH
2-；
R
2Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；Preferably, R
2Selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, R
2For 3-7 membered heterocycloalkyl, preferably 3-7 member oxygen heterocycle alkyl, including but not limited to
It preferably includes, but is not limited to
As the R
2When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；Preferably, Rb is independently selected from F or methyl；
R
3Selected from methoxyl group, chlorine or methyl；
R
4Selected from C
1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In another further preferred embodiment, the present invention provides a kind of formula (IV) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt,
Wherein
R
1For C
1-3Alkyl, preferably methyl；
L is selected from a singly-bound or C
1-3Alkylidene, wherein the C
1-3Alkylidene is optionally replaced by one or more Ra；Preferably, L is selected from singly-bound or-CH
2-；
R
2Selected from hydrogen, C
1-3Alkyl, C
1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；Preferably, R
2Selected from 3-7 member naphthenic base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Or preferably, R
2For 3-7 membered heterocycloalkyl, preferably 3-7 member oxygen heterocycle alkyl, including but not limited to
It preferably includes, but is not limited to
As the R
2When not being hydrogen, optionally replaced by m Rb；
M is 0,1,2,3 or 4；
Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C
1-3Alkyl, C
1-3Alkoxy, C
1-3Hydroxy alkyl, C
1-3Alkyl amino or two (C
1-3Alkyl) amino；Preferably, Rb is independently selected from F or methyl；
R
3Selected from C
1-3Alkoxy, halogen or C
1-3Alkyl；Preferably, R
3Selected from methoxyl group, chlorine or methyl；
R
4Selected from hydrogen, C
1-3Alkyl, 3-7 member naphthenic base, phenyl or thienyl replace: halogen, C wherein the phenyl and thienyl are optionally independently selected by one or more from group below
1-3Alkyl, amino, C
1-3Alkyl amino, two (C
1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C
1-3Alkoxy.
In a further preferred embodiment, R
4Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally independently selected by one or more from fluorine or the group of chlorine replaces.
Specifically, preferred compound is as follows according to the present invention:
There is provided the preparation methods of the compound, its stereoisomer, geometric isomer, tautomer for the second aspect of technical solution of the present invention comprising following steps:
(1) using compound A as starting material, by bromo-reaction prepare compound B；
(2) compound B reacts to obtain compound C with triphosgene；
(3) compound C and N, O- dimethyl hydroxylamine hydrochloride react prepare compound D；
(4) compound E is obtained by methyl-magnesium-bromide attack by compound D；
(5) compound E and 50% amino nitrile reactant aqueous solution obtain the compound F with quinazoline skeleton；
(6) compound F is cyclized through 2,5- acetyl butyryl and protects, and obtains compound G；
(7) compound G reacts removing methyl with alchlor, obtains versatile intermediates H；
(8) intermediate H is reacted with alcohol generation Mitsunobu, or is reacted with halides, and compound I is obtained；
(9) compound I is deprotected to obtain compound J through hydroxylamine hydrochloride；
(10) under Suzuki reaction condition, compound F and compound J and substituted pyridine -3- pinacol borate are coupled to obtain compound, its stereoisomer, geometric isomer, tautomer or the pharmaceutically acceptable salt；Or compound J reacts to obtain corresponding pinacol borate with connection pinacol borate, then is coupled to obtain compound, its stereoisomer, geometric isomer, tautomer or the pharmaceutically acceptable salt with substituted 3- bromopyridine.
The second aspect of technical solution of the present invention additionally provides another preparation method of the compound, its stereoisomer, geometric isomer, tautomer comprising following steps:
(1) using compound A as starting material, by bromo-reaction prepare compound B；
(2) compound B reacts to obtain compound C with triphosgene；
(3) compound C and N, O- dimethyl hydroxylamine hydrochloride react prepare compound D；
(4) compound E is obtained by methyl-magnesium-bromide attack by compound D；
(5) compound E and 50% amino nitrile reactant aqueous solution obtain the compound F with quinazoline skeleton；
(6) compound F is cyclized through 2,5- acetyl butyryl and protects, and obtains compound G；
(7) compound G reacts removing methyl with alchlor, obtains versatile intermediates H；
(8) intermediate H is reacted with alcohol generation Mitsunobu, or is reacted with halides, and compound I is obtained；
(9) compound I is deprotected to obtain compound J through hydroxylamine hydrochloride；
(10) using sodium hydrogen or pyridine as alkali, compound J reacts to obtain compound K with halogenated alkane or alkyl acyl chlorine；
(11) under Suzuki reaction condition, compound K and substituted pyridine -3- pinacol borate are coupled to obtain compound, its stereoisomer, geometric isomer, tautomer or the pharmaceutically acceptable salt.
The second aspect of technical solution of the present invention additionally provides another preparation method of the compound, its stereoisomer, geometric isomer, tautomer comprising following steps:
(1) using compound A as starting material, by bromo-reaction prepare compound B；
(2) compound B reacts to obtain compound C with triphosgene；
(3) compound C and N, O- dimethyl hydroxylamine hydrochloride react prepare compound D；
(4) compound E is obtained by methyl-magnesium-bromide attack by compound D；
(5) compound E and ammonium formate and formamide obtain the compound F with quinazoline skeleton；
(6) compound F reacts removing methyl with alchlor, obtains versatile intermediates G；
(7) intermediate G is reacted with alcohol generation Mitsunobu, or is reacted with halides, and compound H is obtained；
(8) under Suzuki reaction condition, compound H and substituted pyridine -3- pinacol borate are coupled to obtain compound, its stereoisomer, geometric isomer, tautomer or the pharmaceutically acceptable salt；Or compound H reacts to obtain corresponding pinacol borate with connection pinacol borate, then is coupled to obtain compound, its stereoisomer, geometric isomer, tautomer or the pharmaceutically acceptable salt with substituted 3- bromopyridine.
There is provided a kind of pharmaceutical compositions for the third aspect of technical solution of the present invention, described pharmaceutical composition includes the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt and optional pharmaceutically acceptable carrier and/or excipient；Preferably, described pharmaceutical composition also includes the active pharmaceutical ingredient of one or more preventions in addition to the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt and/or treating cancer, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease；Preferably, described pharmaceutical composition be it is pharmaceutically acceptable for prevent and/or treating cancer, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease pharmaceutical preparation.
Another aspect, the present invention also provides a kind of pharmaceutical preparation, it includes at least one compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt and optional pharmaceutically acceptable carrier or/or excipient；Preferably, the pharmaceutical preparation is selected from following pharmaceutical dosage form: parenteral formulation, such as injection solution or suspension；Enteral drug-delivery preparation, such as oral preparation, such as tablet or capsule；Local administration preparation, such as lotion, gel, ointment, emulsion, pernasal preparation, suppository, percutaneous drug administration preparation or eye-drops preparations.
Another aspect, the present invention also provides the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt or described pharmaceutical composition preparation for prevent and/or treating cancer, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease drug in purposes.In other words, the present invention provides a kind of prevention and/or treating cancer, immunity disease, cardiovascular disease, virus infection, inflammation, the methods of metabolism/endocrine dysfunction or neurological disease, this method includes giving the compound, its stereoisomer, geometric isomer, tautomer or the pharmaceutically acceptable salt or described pharmaceutical composition of subject's prevention in need and/or therapeutically effective amount.
Part term used in the present invention is defined as follows below, other undefined terms have meaning well known to skilled artisan.
Halogen refers to fluorine, chlorine, bromine or iodine.
C
1-3Alkylidene refers to the linear chain or branched chain bivalent hydrocarbon radical of the saturation with 1-3 carbon atom.The example of such group includes but is not limited to: methylene (- CH
2), ethylidene (- CH
2CH
2), propylidene (- CH
2CH
2CH
2-)。
C
1-3Alkyl refers to the straight chain and attachment radical of saturated aliphatic alkyl group with 1 to 3 carbon atom.The example of such group includes but is not limited to: methyl, ethyl, propyl, isopropyl.
3-7 member naphthenic base refers to monocycle, condensed, loop coil or the multiring structure of the saturation with 3 to 7 carboatomic ring atoms.The example of such group includes but is not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl and suberyl.
3-7 membered heterocycloalkyl refers to the saturation with 3 to 7 annular atoms or the carbon ring group of part unsaturated (having one or more double bonds and/or three key i.e. in ring), wherein one or more annular atoms be selected from nitrogen, oxygen or S (O) m (wherein m be 0 to 2 integer) hetero atom, it but does not include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon.The specific example of 3-7 member saturated heterocyclic alkyl includes but are not limited to: oxirane base, aziridine base, azetidinyl, oxetanyl, Thietane base, dihydrofuryl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazole alkyl, 1,4- dioxane base, 1,3- dioxane base, 1,3- dithian base, piperidyl, morpholinyl, piperazinyl, dihydro pyranyl, THP trtrahydropyranyl, tetrahydro thiapyran base etc.；Preferably oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, morpholinyl, piperazinyl.
C
1-3Alkoxy refers to-O- alkyl, and wherein the alkyl contains 1 to 3 carbon atom and is straight chain, branch or ring-type.The example of such group includes but is not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy or cyclopropyl oxygroup.
Aryl refers to monocycle or bicyclic aromatic carbocylic groups, usually has 6-10 carbon atom；Such as phenyl or naphthyl.It is preferred that phenyl.
Heteroaryl refers to 5- the or 6- member aromatic heterocycle base of monocycle, including but not limited to: 5- unit's heteroaryl: furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, triazolyl (1, 2, 4- triazolyl, 1, 3, 4- triazolyl or 1, 2, 3- triazolyl), thiadiazolyl group (1, 3, 4- thiadiazolyl group, 1, 2, 5- thiadiazolyl group, 1, 2, 3- thiadiazolyl group or 1, 2, 4- thiadiazolyl group) and oxadiazoles base (1, 3, 4- oxadiazoles base, 1, 2, 5- oxadiazoles base, 1, 2, 3- oxadiazoles base or 1, 2, 4- oxadiazoles base), and 6- unit's heteroaryl: pyridyl group, pyrimidine radicals, pyrazinyl and pyridazinyl, and bicyclic radicals, such as benzofuranyl, benzothienyl, indazole Base, purine radicals, quinolyl, isoquinolyl, phthalazinyl, naphthyridines base, quinoxalinyl (chinocalinyl), quinazolyl, cinnoline base, pteridyl, indolizine base, indyl, isoindolyl.Preferred heteroaryl groups are thienyl, thiazolyl, pyridyl group, pyrimidine radicals.
Singly-bound refers to that two groups of its connection are connected directly, for example when L represents singly-bound in O-L-R indicates that the structure is actually O-R.
" optionally " mean event or environment described later can with but need not occur, which includes that the event or environment occur or not spot occasion.For example, " alkyl being optionally optionally substituted by halogen " mean halogen can with but necessarily exist, which includes the situation that alkyl is optionally substituted by halogen and the situation that alkyl is not optionally substituted by halogen.
If group, such as " R
3" " floating " is portrayed as in formula " on ring A:
Refer to " R
3" be attributable to any atom of ring system, as long as formed rock-steady structure, it is believed that be depicted on an annular atom in annular atom, imply or clearly defined hydrogen be substituted.
Compound of the present invention can be containing one or more chiral centres, with the presence of different stereoisomeric forms in any ratio.All stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereoisomer, enantiomter and atropisomer and their mixture (such as racemic mixture) are within the scope of the present invention.
Compound of the present invention includes its geometric isomer.For example, geometric isomer may be present in these compounds if the compound of the invention contains double bond or condensed ring, then the mixture of the cis- of them, trans forms and cis and trans is included within the scope of the present invention.
Compound of the present invention includes its tautomer.Tautomer refers to the constitutional isomer of the different-energy mutually converted via low energy barrier, such as keto-enol and imine-enamine tautomerism.
Compound of the present invention further includes its compound isotopically labelled, and what wherein one or more atoms were naturally found has same atoms ordinal number but the atom substitution of different atomic masses or mass number.Example includes but is not limited to: hydrogen isotope
2H and
3H；Carbon isotope
11C、
13C and
14C；Chlorine isotope
36Cl；Fluorine isotope
18F；Iodine isotope
123I and
125I；Nitrogen isotope
13N and
15N；Oxygen isotope
15O、
17O and
18O；Phosphorus isotope
32P and sulfur isotope
35S。
The various hydrates and solvate of compound or its salt of the present invention and its polymorphic (polymorphisms) are intended to be included within the scope of the present invention.
The prodrug of compound of the present invention is intended to be included within the scope of the present invention.Certain derivatives itself of compound of the present invention have weaker pharmacological activity or no pharmacological activity, but when in these derivative donors or when giving on body, they can be converted to the compound of the present invention with pharmacological activity for example, by modes such as hydrolytic cleavages, these derivatives are known as " prodrug ".Further information about prodrug purposes can be in Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T.Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, it is found in 1987 (ed.E.B.Roche, American Pharmaceutical Association).
Compound of the present invention includes its pharmaceutically acceptable salt.Pharmaceutically acceptable salt refers to for salt pharmaceutically acceptable and with pharmacological activity needed for parent compound.Pharmaceutically acceptable salt is described in detail in Berge et al. in J.Pharma.Sci., 1977,66,1-19, and the document is incorporated herein by reference.Compound of the present invention can contain enough acidic-groups, enough basic groups or the functional group for having both both types, and correspondingly form pharmaceutically acceptable salt with some inorganic or organic base or inorganic and organic acid reaction.The example of pharmaceutically acceptable salt includes sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, single hydrogen orthophosphate, dihydrogen orthophosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromate, hydriodate, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, butine -1, 4- diacid salt, hexin -1, 6- diacid salt, benzoate, chloro-benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxy benzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, citrate , lactate, gamma hydroxybutyrate, oxyacetate, tartrate, methane sulfonates, propane sulfonic acid salt, naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
Compound of the present invention as drug in use, be usually in the form of pharmaceutical composition be administered.Therefore, the pharmaceutical composition of compound of the present invention and pharmaceutically acceptable carrier, diluent or excipient is also included within the scope of the present invention.Carrier used herein, auxiliary agent, excipient include any and all solvents, diluent or other liquid excipients, dispersing agent or suspending agent, surfactant, isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc. for being suitable for desired particular dosage form.In Remington:The Science and Practice of Pharmacy, 21
stEdition, 2005, ed.D.B.Troy, Lippincott Williams&Wilkins, Philadelphia, with Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, in New York, the various carriers for preparing pharmaceutically acceptable composition and the known technology for its preparation are disclosed, their content is all incorporated by reference herein.
Composition of the present invention can be administered by being suitable for any approach of illness to be treated.Especially it is administered through following form: it is parenteral, such as with Injectable solution or suspended form；It is enteral such as oral, such as in the form of a tablet or capsule；Part, such as in the form of lotion, gel, ointment or emulsion or with nose or suppository form.Local application is for example to be applied to skin.Another form of local administration is to deliver medicine to eye.
Pharmaceutical composition can be applied with solid, semisolid, liquid or gaseous form, or can be in dry powder, such as lyophilized form.The form that pharmaceutical composition can be packaged as convenient for transmitting, including such as solid dosage forms, such as capsule, anther sac, cachet, gelatin, paper, tablet, suppository, granule, pill, lozenge and pastille.The type of packaging will generally depend on administration method.It is also covered by the preparation and percutaneous preparation of implantable sustained release.
Can include but is not limited to as some examples of the material of pharmaceutically acceptable carrier: ion-exchanger, aluminium oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumins), buffer substance (such as phosphate), glycine, sorbic acid or potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax class, polyethylene-polyoxypropylene block copolymer, lanolin, carbohydrate (such as lactose, dextrose and saccharose), starch (such as cornstarch and potato starch), cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Powdered tragacanth；Malt；Gelatin；Talcum powder；Excipient, such as cocoa butter and suppository wax；Oils, such as peanut oil, cottonseed oil；Safflower oil；Sesame oil；Olive oil；Corn oil and soybean oil；Glycol, such as propylene glycol or polyethylene glycol；Esters, such as ethyl oleate and ethyl laurate；Agar；Buffer, such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic saline solution；Ringer's solution；Ethyl alcohol；And phosphate buffer and other nontoxic compatible lubricants, such as NaLS and magnesium stearate.According to the judgement of formulation scientist, there may also be colorant, releasing agent, coating agent, sweetener, flavoring agent and aromatic, preservative and antioxidants in the composition.
Compound of the present invention can be used alone or use with the therapeutic agent of other treatments disease of the present invention or illness (such as cancer).In certain embodiments, compound of the present invention is combined in medicine composition with second of compound with anti-hyperproliferation property or for treatment height proliferative diseases (such as cancer), or is combined in dosage regimen as combination therapy.The second compound of pharmaceutical combination preparations or Dosing schedules preferably has the activity complementary with compound of the present invention, so that they will not mutually have an adverse effect.Such compound is suitably present in combination with effectively measuring to plan purpose.In one embodiment, the compound of the present invention is combined with other anti-tumor drugs.The anti-tumor drug includes: alkylating agents, includes but are not limited to cyclophosphamide, mustargen, melphalan, chlorambucil, Carmustine；Metal platinum class includes but are not limited to carboplatin, cis-platinum, oxaliplatin；Topoisomerase enzyme inhibitor includes but are not limited to Topotecan, camptothecine, topotecan, Irinotecan；Antibiotics include but are not limited to fennel ciclamicin, actinomycin D, daunorubicin, adriamycin, mitoxantrone, bleomycin, plicamycin；Anti- micro-pipe or antimitotic agent include but are not limited to taxol, vinorelbine, docetaxel, Doxorubicin；Antimetabolic species include but are not limited to fluorouracil, methotrexate (MTX), cytarabine, mercaptopurine (mecaptopurine), thioguanine and gemcitabine；Antibody class includes but are not limited to Trastuzumab, bevacizumab；Steroids includes but are not limited to Letrozole (Letrazole), R 83842 (vorazole), tamoxifen, Toremifene, fulvestrant, Flutamide, Nilutamide, Triptorelin；Kinase inhibitor class, EGFR kinase inhibitor include but are not limited to Gefitinib (gefitinib), Tarceva (erlotinib), Lapatinib (lapatinib), Afatinib (afatinib)；It is rich for Buddhist nun (Cabozantinib), pazopanib (Pazopanib), Vande Thani (vandetanib), pazopanib (axitinib) to include but are not limited to Sorafenib (Sorafenib), Rui Gefeini (Regorafenib), Sutent (Sunitinib), card for VEGFR inhibitor；ALK inhibitor includes but are not limited to gram azoles for Buddhist nun (Crizotinib), Ceritinib (ceritinib), Alectinib；Bcr-Abl inhibitor includes but are not limited to Imatinib (Imatinib), pa is received for Buddhist nun (Ponatinib), nilotinib (Nilotinib), Dasatinib (Dasatinib)；BTK inhibitor is included but are not limited to according to Shandong for Buddhist nun (Ibrutinib)；B-RAF inhibitor includes but are not limited to Wei Luofeini (Vemurafenib)；Cell cycle protein dependent kinase CDK4/6 inhibitor, Pa Boxini (Palbociclib)；MTOR inhibitors include but are not limited to rapamycin (rapamycin), everolimus (everolimus)；Deacetylase inhibitor includes but are not limited to Vorinostat (vorinostat)；PD1/PDL1 antibody, Keytruda (Pembrolizumab), Opdivo (Nivolumab).
There is provided compound described in first aspect, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salts for the fourth aspect of technical solution of the present invention, or the application in the drug of disease of the third aspect described pharmaceutical composition in preparation for preventing and/or treating PI3K mediation, wherein, the disease that the PI3K is mediated includes cancer, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease.
Advantageous effects: the compounds of this invention has very high inhibitory activity to PI3K alpha kinase；There is very strong external antiproliferative activity to the human lung carcinoma cell NCI-H460 of high expression PI3Kalfa, internal pharmacodynamic study shows, no matter therefrom the compounds of this invention in knurl product or weight, to human lung cancer NCI-H460 and human gastric cancer HGC-27 nude mice by subcutaneous heteroplastic transplantation tumor growth with significant inhibiting effect.
Fig. 1 is tumor growth curve, which show embodiment 9 to human lung cancer NCI-H460 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect.
Fig. 2 is tumor growth curve, which show embodiment 44 to human lung cancer NCI-H460 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect.
Fig. 3 is tumor growth curve, which show embodiment 32 to human gastric cancer HGC-27 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect.
The following is specific embodiments of the present invention, is further described to technical solution of the present invention, but protection scope of the present invention is not limited to these examples.It is all to be included in protection scope of the present invention without departing substantially from the change of present inventive concept or equivalent substitute.
In the examples below, it is annotated unless otherwise structural formula or chemical name, the molecule with single chiral center exists in the form of racemic mixtures.It is annotated unless otherwise structural formula or chemical name, there is the molecule of two or more chiral centres to exist in the form of the racemic mixture of diastereoisomer for those.Single enantiomter/diastereoisomer can be obtained by method known to those skilled in the art.
Preparation method
Compound of the present invention can be synthesized according to synthetic schemes herein and/or technology well known in the art.For example, compound provided by the invention can be prepared according to following universal synthesis method.
Universal synthesis method
Specifically, in universal synthesis method, quinazoline compounds of the present invention can be reacted by 10 steps to be prepared.For example, starting material A is converted into compound B through bromo-reaction, react to obtain compound C with triphosgene.Compound C and N, O- dimethyl hydroxylamine hydrochloride react to obtain compound D, generate compound E by methyl-magnesium-bromide attack.Compound E and 50% amino nitrile reactant aqueous solution obtain the compound F with quinazoline skeleton, then protect its amino group by being cyclized with 2,5- acetyl butyryl.Gained compound G reacts removing methyl with alchlor, obtains versatile intermediates H.Intermediate H occurs Mitsunobu with various alcohol and reacts, or reacts with various halides, obtains compound I, is deprotected to obtain compound J through hydroxylamine hydrochloride.Under Suzuki reaction condition well known by persons skilled in the art, compound F and compound J and substituted pyridine -3- pinacol borate are coupled to obtain compound 1-28.Alternatively, compound J reacts to obtain corresponding pinacol borate with connection pinacol borate, then is coupled to obtain final product compound 1-28 with substituted 3- bromopyridine.
In another universal synthesis method, quinazoline compounds of the present invention can be reacted by 11 steps to be prepared.For example, starting material A is converted into compound B through bromo-reaction, react to obtain compound C with triphosgene.Compound C and N, O- dimethyl hydroxylamine hydrochloride react to obtain compound D, generate compound E by methyl-magnesium-bromide attack.Compound E and 50% amino nitrile reactant aqueous solution obtain the compound F with quinazoline skeleton, then protect its amino group by being cyclized with 2,5- acetyl butyryl.Gained compound G reacts removing methyl with alchlor, obtains versatile intermediates H.Intermediate H occurs Mitsunobu with various alcohol and reacts, or reacts with various halides, obtains compound I, is deprotected to obtain compound J through hydroxylamine hydrochloride.Using sodium hydrogen or pyridine as alkali, compound J reacts to obtain compound K with halogenated alkane or alkyl acyl chlorine.Under Suzuki reaction condition well known by persons skilled in the art, compound K and substituted pyridine -3- pinacol borate are coupled to obtain compound 29-43.
In another universal synthesis method, quinazoline compounds of the present invention can be reacted by 8 steps to be prepared.For example, starting material A is converted into compound B through bromo-reaction, react to obtain compound C with triphosgene.Compound C and N, O- dimethyl hydroxylamine hydrochloride react to obtain compound D, generate compound E by methyl-magnesium-bromide attack.Compound E and ammonium formate and formamide obtain the compound F with quinazoline skeleton, then removing methyl is reacted with alchlor, obtain versatile intermediates G.Intermediate G occurs Mitsunobu with various alcohol and reacts, or reacts with various halides, obtains compound H.Under Suzuki reaction condition well known by persons skilled in the art, compound F and compound H and substituted pyridine -3- pinacol borate are coupled to obtain compound 44-73.Alternatively, compound H reacts to obtain corresponding aryl boric acid pinacol ester with connection pinacol borate, then is coupled to obtain final product compound 44-73 with substituted 3- bromopyridine.
Compound of the present invention can be synthesized according to one or more synthetic schemes herein and/or technology well known in the art.Those skilled in the art will appreciate that the synthetic method for the certain embodiments being described in detail in the present invention, can be readily adapted for use in synthesis other embodiments.In some embodiments, compound as described herein can be prepared by the appropriately combined of synthetic method well known in the art.Many starting materials and other reagents are purchased from commercial supplier, such as AlfaAesar (China) Chemical Co., Ltd., or are easily prepared using synthetic method commonly used in the art.
1It is recorded on the instrument that H H NMR spectroscopy is operated at 400MHz or 500MHz.H H NMR spectroscopy is obtained (reported with ppm) in the form of a solution, and CDCl is used
3(7.26ppm) or DMSO-d
6(2.50ppm) or internal standard tetramethylsilane (0.00ppm) are used as reference standard.When reporting peak multiplicity, use following abbreviation: s (unimodal), d (bimodal), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplets).The coupling Changshu provided is in terms of hertz (Hz).
When needing, (R)-and (S)-isomers of non-restrictive illustrative compound, if it does, can split by methods known to those skilled in the art, such as by forming diastereomeric salt or compound, can be separated for example, by crystallization；By forming diastereoisomerism derivative, can be separated for example, by crystallization or chromatography；Make an enantiomter and the selective reaction of enantiomter specific reagent, then separates modified and unmodified enantiomter；Or chromatographic isolation is carried out in the chiral environment of such as chiral chromatographic column.Alternatively, specific enantiomter can carry out asymmetric syntheses by using optical activity reagent, substrate, catalyst or solvent, or convert another for an enantiomter by asymmetric transformation to prepare.
In following preparation method and example, " Me " refers to methyl, and " Et " refers to ethyl, and " Ph " refers to phenyl, and " PE " refers to petroleum ether, and " EtOAc " refers to ethyl acetate, and " MeOH " refers to methanol, and " DMF " refers to n,N-Dimethylformamide, " CDCl
3" refer to deuterated chloroform, " DMSO-d
6" refer to deuterated dimethyl sulfoxide, " NMP " refers to 1-Methyl-2-Pyrrolidone, and " DCM " refers to methylene chloride, and " DCE " refers to 1,2- dichloroethanes, and " THF " refers to tetrahydrofuran, and " HCl " refers to hydrochloric acid, and " TsOH " refers to p-methyl benzenesulfonic acid, " AlCl
3" refer to alchlor, " TEA " refers to triethylamine, and " NBS " refers to N- bromo-succinimide, " Na
2SO
4" refer to sodium sulphate, " K
2CO
3" refer to potassium carbonate, " MeMgBr " refers to methyl-magnesium-bromide, and " DEAD " refers to diethyl azodiformate, " PPh
3" refer to triphenylphosphine, " PdCl
2(dppf) " refer to [1; bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, " Ar " refers to argon gas, and " M " refers to molarity; " rt " refers to room temperature; " min " refers to minute, and " h " refers to hour, and " mL " refers to milliliter; " mmol " refers to mM; " μM " refers to micromole, and " nM " refers to nanomole, and " DEG C " refers to degree Celsius.
The preparation of versatile intermediates (H)
The preparation of the bromo- 3- methoxy benzoic acid (B) of step 1:2- amino -5-
Divide 5 batches for NBS (28.04g, 157.5mmol) in 20min and is added to 2- amino -3- methoxy benzoic acid (A) (25.08g, 150mmol) in the solution in DMF (200mL).2h is stirred at room temperature in the reaction mixture of generation.With water (2L) diluted reaction mixture, (500mL × 4) are extracted with EtOAc.The organic layer merged is washed with water (500mL × 3) and saline solution (500mL), uses anhydrous Na
2SO
4It dries, filters, being concentrated to get product crude product (B) is dark brown solid (35g, yield 95%), is directly used in without further purification in next step.
1H NMR(400MHz,DMSO-d
6) δ 7.42 (d, J=2.2Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 3.84 (s, 3H).
The preparation of bromo- 8- methoxyl group -2H- benzo [d] [1,3] oxazines -2,4 (the 1H)-diketone (C) of step 2:6-
By the mixture reflux 3h in compound (B) (35g, 142.2mmol) and triphosgene (32mg, 107.8mmol) Yu Wushui THF (350mL).After being cooled to room temperature, the solid of generation is collected by filtration, is washed with PE/EtOAc solution (1:1, v/v, 200mL), being dried to obtain product (C) is faint yellow solid (30.78g, yield 80%).
1H NMR(400MHz,DMSO-d
6) δ 11.43 (s, 1H), 7.56 (d, J=2.0Hz, 1H), 7.55 (d, J=2.0Hz, 1H), 3.92 (s, 3H).
The step 3:2- amino bromo- N of -5-, the preparation of 3- Dimethoxy-N-methyl benzamide (D)
By compound (C) (30.78g, 113.12mmol), N, O- dimethyl hydroxylamine hydrochloride (16.55g, 169.68mmol) it is refluxed overnight with the mixture of TEA (26.7mL, 192.3mmol) in dioxane (300mL).Decompression boils off volatile matter.With water (500mL) diluted reaction mixture, extracted with EtOAc (200mL × 3).The organic layer merged is washed with water (200mL × 2) and saline solution (200mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow oil (29.73g, yield 91%) that residue, which obtains product (D) through flash column chromatography (silica gel, PE/EtOAc=4:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 7.01 (d, J=2.0Hz, 1H), 6.97 (d, J=2.0Hz, 1H), 5.10 (br s, 2H), 3.82 (s, 3H), 3.53 (s, 3H), 3.22 (s, 3H).
The preparation of step 4:1- (the bromo- 3- methoxyphenyl of 2- amino -5-) ethyl ketone (E)
To compound (D) (29.73g in argon atmosphere at -20 DEG C, 103mmol) in the solution in anhydrous tetrahydro furan (300mL), methyl-magnesium-bromide (1M tetrahydrofuran solution, 206mL, 206mmol) is slowly added dropwise in 30min.The reaction mixture of generation is stirred into 30min at -20 DEG C, is then quenched with saturated aqueous ammonium chloride.With water (1L) diluted reaction mixture, extracted with EtOAc (300mL × 3).The organic layer merged is washed with water (300mL × 2) and saline solution (300mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow oil (6.5g, yield 26%) that residue, which obtains product (E) through flash column chromatography (silica gel, PE/EtOAc=15:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 7.50 (d, J=2.0Hz, 1H), 7.08 (d, J=2.0Hz, 1H), 7.04 (s, 2H), 3.84 (s, 3H), 2.51 (s, 3H).
The preparation of the bromo- 8- methoxyl group -4- methylquinazolin -2- amine (F) of step 5:6-
The mixture of compound (E) (7.41g, 30.36mmol) and concentrated hydrochloric acid (10mL) in 50% amino nitrile aqueous solution (74mL) is stirred into 15min at 120 DEG C.Reaction mixture is cooled to room temperature, it is diluted with water (300mL), the solid of generation is collected by filtration, is washed with water (100mL) and ethyl alcohol (30mL), being dried to obtain product (F) is faint yellow solid (8.00g, yield 98%).
1H NMR(400MHz,DMSO-d
6) δ 7.67 (d, J=2.0Hz, 1H), 7.20 (d, J=2.0Hz, 1H), 6.90 (br s, 2H), 3.88 (s, 3H), 2.67 (s, 3H).
The preparation of the bromo- 2- of step 6:6- (2,5- dimethyl -1H- pyrroles -1- base) -8- methoxyl group -4- methylquinazolin (G)
By compound (F) (8.00g, 29.84mmol), 2,5- acetyl butyryl (13.61g, 119.36mmol), with mixture of the p-methyl benzenesulfonic acid monohydrate (0.568g, 2.98mmol) in NMP (80mL) and toluene (80mL) reflux water-dividing 6h at 160 DEG C.Reaction mixture is cooled to room temperature, decompression boils off toluene, is diluted with water (400mL), extracts (100mL × 3) with EtOAc.The organic layer merged is washed with water (100mL × 3) and saline solution (100mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow solid (8.95g, yield 87%) that residue, which obtains product (G) through flash column chromatography (silica gel, PE/EtOAc=30:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 8.04 (d, J=1.8Hz, 1H), 7.57 (d, J=1.8Hz, 1H), 5.84 (s, 2H), 4.01 (s, 3H), 2.92 (s, 3H), 2.30 (s, 6H).
The preparation of the bromo- 2- of step 7:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin -8- phenol (H)
AlCl is added in the solution in DCE (300mL) to compound (G) (3.27g, 9.56mmol)
3(3.83g, 28.68mmol).The reaction mixture of generation is stirred into 1.5h at 80 DEG C.Reaction mixture is cooled to room temperature, is diluted with water (300mL), extracts (300mL × 2) with DCM.The organic layer merged is washed with water (200mL) and saline solution (100mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow solid (2.41g, yield 77%) that residue, which obtains product (H) through flash column chromatography (silica gel, PE/EtOAc=50:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.64 (s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.44 (d, J=2.0Hz, 1H), 5.84 (s, 2H), 2.91 (s, 3H), 2.29 (s, 6H).
The preparation of versatile intermediates (M)
The preparation of the bromo- 8- methoxyl group -4- methylquinazolin (L) of step 1:6-
By compound (E) (3.328g, 13.63mmol) and ammonium formate (3.271g, 54.52mmol), the reaction mixture in formamide (34mL) stirs 7h at 150 DEG C.Reaction mixture is cooled to room temperature, is diluted with water (150mL), (100mL × 3) is extracted with ethyl acetate.The organic layer merged is washed with water (100mL × 2) and saline solution (100mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow solid (2.492g, yield 72.2%) that residue, which obtains product (L) through flash column chromatography (silica gel, petrol ether/ethyl acetate=10:1 and then 4:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 9.09 (s, 1H), 8.00 (d, J=1.9Hz, 1H), 7.54 (d, J=1.9Hz, 1H), 4.00 (s, 3H), 2.87 (s, 3H).
The preparation of the bromo- 4- methylquinazolin -8- phenol (M) of step 6:6-
Alchlor (6.90g, 51.69mmol) is added in the solution in 1,2- dichloroethanes (390mL) to compound (L) (4.36g, 17.23mmol).The reaction mixture of generation is stirred into 1.5h at 80 DEG C.Reaction mixture is cooled to room temperature, is diluted with water (400mL), (300mL × 2) is extracted with dichloromethane.The organic layer merged is washed with water (200mL) and saline solution (100mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow solid (3.02g, yield 73.3%) that residue, which obtains product (M) through flash column chromatography (silica gel, DCM/MeOH=100:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.83 (s, 1H), 9.10 (s, 1H), 7.87 (d, J=2.0Hz, 1H), 7.41 (d, J=2.0Hz, 1H), 2.86 (s, 3H).
Embodiment 1:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (1)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline (I-1)
At room temperature to compound (the H) (3.322g that stirred in argon atmosphere, 10mmol), triphenylphosphine (3.148g, 12mmol) and tetrahydro -2H- pyrans -4- alcohol (1.226g, diethyl azodiformate (2.09g, 12mmol) 12mmol) is added in the solution in anhydrous tetrahydro furan (50mL).The reaction mixture of generation is stirred at room temperature overnight.It is added silica gel (10g), by evaporated under reduced pressure in the mixture of generation.It is yellow oil (2.097g, yield 50%) that residue, which obtains product (I-1) through flash column chromatography (silica gel, PE/EtOAc=10:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 8.04 (d, J=1.9Hz, 1H), 7.70 (d, J=1.8Hz, 1H), 5.86 (s, 2H), 5.01-4.91 (m, 1H), 3.94-3.80 (m, 2H), 3.56 (ddd, J=11.2,8.0,3.2Hz, 2H), (2.92 s, 3H), 2.36 (s, 3H), 2.09-1.94 (m, 2H), 1.77-1.65 (m, 2H).
The preparation of the bromo- 4- methyl -8- of step 2:6- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- amine (J-1)
By compound (I-1) (2.082g, 5.0mmol) and hydroxylamine hydrochloride (1.734g, 25mmol), the mixture in ethyl alcohol (40mL) and water (4mL) is refluxed overnight.It by the mixture evaporated under reduced pressure of generation, is diluted with water (100mL), is neutralized with saturated sodium bicarbonate aqueous solution, extracted with DCM (50mL × 3).The organic layer merged is washed with water (50mL) and saline solution (50mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow oil (0.667g, yield 39%) that residue, which obtains product (J-1) through flash column chromatography (silica gel, DCM/MeOH=50:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 7.68 (d, J=2.0Hz, 1H), 7.36 (d, J=2.0Hz, 1H), 6.85 (s, 2H), 4.82-4.73 (m, 1H), 3.94-3.87 (m, 2H), 3.53-3.45 (m, 2H), 2.65 (s, 3H), 2.05-1.96 (m, 2H), 1.68-1.58 (m, 2H).
MS(ESI+)m/z 337.8,339.8[M+H]
+。
The preparation of step 3:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (1)
By compound (J-1) (538mg, 1.59mmol), N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide (814mg, it 1.91mmol) deaerates with the mixture of 2M wet chemical (2.40mL, 4.8mmol) in dioxane (15mL), PdCl is then added
2(dppf) (58mg, 0.08mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with EtOAc (50mL) and water (50mL), being acidified to pH with 2M hydrochloric acid is 5-6.Two-phase is separated, extracts (30mL × 2) water layer with EtOAc.The organic layer merged is washed with water (50mL) and saline solution (50mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow foamy solid (400mg, yield 45%) that residue, which obtains product (1) through flash column chromatography (silica gel, DCM/MeOH=50:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.29 (s, 1H), 8.44 (d, J=2.2Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.76 (dt, J=8.4,2.4Hz, 1H), 7.66 (d, J=1.2Hz, 1H), 7.64-7.54 (m, 1H), 7.46 (d, J=1.2Hz, 1H), 7.23 (dt, J=8.6,2.0Hz, 1H), (6.79 s, 2H), 4.97-4.82 (m, 1H), 3.98-3.89 (m, 2H), (3.64 s, 3H), 3.56-3.45 (m, 2H), 2.75 (s, 3H), 2.10-1.99 (m, 2H), 1.75- 1.58 (m, 2H).
MS(ESI+)m/z 558.2[M+H]
+。
Embodiment 2:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) chloro- 4- fluorobenzenesulfonamide (2) of -2-
According to the method for step 3 in embodiment 1, by compound (J-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) the chloro- 4- fluorobenzenesulfonamide prepare compound (2) of -2-.
1H NMR(400MHz,DMSO-d
6) δ 10.17 (s, 1H), 8.42 (d, J=2.3Hz, 1H), 7.94 (dd, J=8.8,6.0Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.76 (dd, J=8.8,2.4Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.43 (d, J=1.4Hz, 1H), 7.40-7.33 (m, 1H), 6.79 (s, 2H), 4.94-4.81 (m, 1H), 3.98-3.89 (m, 2H), 3.66 (s, 3H), 3.57-3.45 (m, 2H), 2.75 (s, 3H), 2.10-1.99 (m, 2H), 1.74 - 1.58 (m, 2H).
MS(ESI+)m/z 574.1[M+H]
+。
Embodiment 3:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -4- fluorobenzenesulfonamide (3)
According to the method for step 3 in embodiment 1, by compound (J-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -4- fluorobenzenesulfonamide prepare compound (3).
1H NMR(400MHz,DMSO-d
6) δ 10.04 (s, 1H), 8.39 (d, J=2.4Hz, 1H), 7.88 (d, J=2.4Hz, 1H), 7.86-7.79 (m, 2H), 7.61 (d, J=1.8Hz, 1H), 7.47-7.39 (m, 3H), 6.79 (s, 2H), 4.95-4.82 (m, 1H), 3.98-3.89 (m, 2H), 3.65 (s, 3H), 3.56-3.42 (m, 2H), 2.75 (s, 3H), 2.11-1.98 (m, 2H), 1.74-1.59 (m, 2H).
MS(ESI+)m/z 540.2[M+H]
+。
Embodiment 4:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -5- chlorothiophene -2- sulfonamide (4)
According to the method for step 3 in embodiment 1, by compound (J-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide prepare compound (4).
1H NMR(400MHz,DMSO-d
6) δ 10.34 (s, 1H), 8.46 (d, J=2.4Hz, 1H), 7.95 (d, J=2.4Hz, 1H), (7.67 d, J=1.6Hz, 1H), 7.47 (d, J=1.6Hz, 1H), 7.39 (d, J=4.0Hz, 1H), 7.24 (d, J=4.0Hz, 1H), 6.80 (s, 2H), 4.95-4.84 (m, 1H), 4.00-3.86 (m, 2H), 3.74 (s, 3H), 3.58-3.45 (m, 2H), (2.76 s, 3H), 2.11-2.00 (m, 2H), 1.77-1.60 (m, 2H).
MS(ESI+)m/z 562.1[M+H]
+。
Embodiment 5:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) Methanesulfomide (5)
According to the method for step 3 in embodiment 1, by compound (J-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (5).
1H NMR(400MHz,DMSO-d
6) δ 9.34 (s, 1H), 8.43 (d, J=2.3Hz, 1H), 7.95 (d, J=2.3Hz, 1H), 7.70 (d, J=1.6Hz, 1H), 7.47 (d, J=1.6Hz, 1H), 6.77 (s, 2H), 4.97-4.81 (m, 1H), 3.98 (s, 3H), 3.96-3.88 (m, 2H), 3.55-3.44 (m, 2H), 3.08 (s, 3H), 2.75 (s, 3H), 2.10-2.00 (m, 2H), 1.76-1.57 (m, 2H).
MS(ESI+)m/z 460.2[M+H]
+。
Embodiment 6:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) cyclopropylsulfonamide (6)
According to the method for step 3 in embodiment 1, by compound (J-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) cyclopropylsulfonamide prepare compound (6).
1H NMR(400MHz,DMSO-d
6) δ 9.37 (s, 1H), 8.43 (d, J=2.3Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.69 (d, J=1.8Hz, 1H), 7.47 (d, J=1.8Hz, 1H), (6.78 s, 2H), 4.97-4.80 (m, 1H), 3.98 (s, 3H), 3.96-3.88 (m, 2H), 3.57-3.44 (m, 2H), 2.83-2.70 (m, 4H), 2.12-1.98 (m, 2H), 1.74-1.61 (m, 2H), 1.01-0.89 (m, 4H).
MS(ESI+)m/z 486.2[M+H]
+。
Embodiment 7:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- picoline -3- base) -2,4 difluorobenzene sulfonamide (7)
By compound (J-1) (75mg, 0.22mmol), acetic anhydride potassium (65mg, 0.66mmol) and connection pinacol borate (64mg, 0.25mmol) the mixture degassing in dioxane (8mL), is then added PdCl
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, stir 4h in argon atmosphere at 100 DEG C.After being cooled to room temperature, N- (5- bromine-2-methylpyridine -3- base) -2,4- difluorobenzenesulfonamide (91mg, 0.25mmol) and 2M wet chemical (0.44mL, 0.88mmol) are added into the mixture of generation.The mixture of generation is deaerated, PdCl is then added
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with EtOAc (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is separated, extracts (30mL × 2) water layer with EtOAc.The organic layer merged is washed with water (50mL) and saline solution (50mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow foamy solid (35mg, yield 29%) that residue, which is prepared thin-layer chromatography (DCM/MeOH/ ammonium hydroxide=15:1:0.1, v/v) purifying and obtains product (7),.
1H NMR(400MHz,DMSO-d
6) δ 10.45 (s, 1H), 8.73 (s, 1H), 7.80 (dt, J=8.4,6.4Hz, 1H), 7.72-7.54 (m, 3H), 7.40 (s, 1H), 7.27 (dt, J=8.4,2.0Hz, 1H), 6.84 (s, 2H), 4.91-4.80 (m, 1H), 3.98-3.88 (m, 2H), 3.58-3.43 (m, 2H), 2.73 (s, 3H), 2.33 (s, 3H), 2.08-1.98 (m, 2H), 1.77-1.58 (m, 2H).
MS(ESI+)m/z 542.2[M+H]
+。
Embodiment 8:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- chloropyridine -3- base) -4- fluorobenzenesulfonamide (8)
By compound (J-1) (75mg, 0.22mmol), acetic anhydride potassium (65mg, 0.66mmol) and connection pinacol borate (64mg, 0.25mmol) the mixture degassing in dioxane (8mL), is then added PdCl
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, stir 4h in argon atmosphere at 100 DEG C.After being cooled to room temperature, N- (the bromo- 2- chloropyridine -3- base of 5-) -4- fluorobenzenesulfonamide (91mg, 0.25mmol) and 2M wet chemical (0.44mL, 0.88mmol) are added into the mixture of generation.The mixture of generation is deaerated, PdCl is then added
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with EtOAc (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is separated, extracts (30mL × 2) water layer with EtOAc.The organic layer merged is washed with water (50mL) and saline solution (50mL), uses anhydrous Na
2SO
4It dries, filters, is concentrated.It is yellow foamy solid (30mg, yield 25%) that residue, which is prepared thin-layer chromatography (DCM/MeOH/ ammonium hydroxide=15:1:0.1, v/v) purifying and obtains product (8),.
1H NMR(400MHz,DMSO-d
6) δ 10.53 (s, 1H), 8.67 (d, J=1.7Hz, 1H), 7.99 (d, J=2.3Hz, 1H), 7.87-7.77 (m, 2H), 7.71 (d, J=1.7Hz, 1H), 7.51-7.40 (m, 3H), 6.90 (s, 2H), 4.95-4.82 (m, 1H), 3.98-3.88 (m, 2H), 3.57-3.44 (m, 2H), 2.76 (s, 3H), 2.12-1.95 (m, 2H), 1.75-1.59 (m, 2H).
MS(ESI+)m/z 544.1[M+H]
+。
Embodiment 9:(R)-N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (9)
Step 1:(R) the bromo- 2- of -6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline (I-9) preparation
According to the method for step 1 in embodiment 1, by compound (H) and (S)-tetrahydrofuran -3- alcohol prepare compound (I-9).
1H NMR(400MHz,CDCl
3) δ 7.82 (d, J=1.6Hz, 1H), 7.22 (d, J=1.6Hz, 1H), (5.91 s, 2H), 5.22-5.14 (m, 1H), 4.18-3.94 (m, 4H), 2.91 (s, 3H), 2.45 (s, 6H), 2.33-2.26 (m, 2H).
Step 2:(R) the bromo- 4- methyl -8- of -6- ((tetrahydrofuran -3- base) oxygroup) quinazoline -2- amine (J-9) preparation
According to the method for step 2 in embodiment 1, by compound (I-9) prepare compound (J-9).
1H NMR(400MHz,DMSO-d
6) δ 7.69 (d, J=2.0Hz, 1H), 7.21 (d, J=2.0Hz, 1H), 6.89 (s, 2H), 5.25-5.18 (m, 1H), 3.97-3.83 (m, 3H), 3.80-3.72 (m, 1H), 2.66 (s, 3H), 2.33-2.21 (m, 1H), 2.05-1.93 (m, 1H).
Step 3:(R)-N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (9) preparation
According to the method for step 3 in embodiment 1, by compound (J-9) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (9).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.82-7.72 (m, 1H), 7.67 (d, J=1.5Hz, 1H), 7.64-7.53 (m, 1H), 7.32 (d, J=1.5Hz, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 6.83 (s, 2H), 5.43-5.29 (m, 1H), 4.02-3.85 (m, 3H), 3.83-3.74 (m, 1H), 3.65 (s, 3H), 2.75 (s, 3H), 2.35-2.22 (m, 1H), 2.08-2.01 (m, 1 H).
MS(ESI+)m/z 544.1[M+H]
+。
Embodiment 10:(R)-N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) Methanesulfomide (10)
According to the method for step 3 in embodiment 1, by compound (J-9) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (10).
1H NMR(400MHz,DMSO-d
6) δ 9.35 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.71 (d, J=1.6Hz, 1H), 7.34 (d, J=1.6Hz, 1H), 6.83 (s, 2H), 5.39-5.33 (m, 1H), 3.98 (s, 3H), 3.97-3.87 (m, 3H), 3.82-3.74 (m, 1H), 3.09 (s, 3H), 2.75 (s, 3H), 2.34-2.22 (m, 1H), 2.12-2.00 (m, 1H).
MS(ESI+)m/z 446.1[M+H]
+。
Embodiment 11:(S)-N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (11)
Step 1:(S) the bromo- 2- of -6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline (I-11) preparation
According to the method for step 1 in embodiment 1, by compound (H) and (R)-tetrahydrofuran -3- alcohol prepare compound (I-11).
1H NMR(400MHz,DMSO-d
6) δ 8.05 (d, J=1.8Hz, 1H), 7.58 (d, J=1.8Hz, 1H), 5.85 (s, 2H), 5.38-5.31 (m, 1H), 4.06-3.75 (m, 4H), 2.92 (s, 3H), (2.34 s, 6H), 2.32-2.24 (m, 1H), 2.13-2.02 (m, 1H).
Step 2:(S) the bromo- 4- methyl -8- of -6- ((tetrahydrofuran -3- base) oxygroup) quinazoline -2- amine (J-11) preparation
According to the method for step 2 in embodiment 1, by compound (I-11) prepare compound (J-11).
1H NMR(400MHz,DMSO-d
6) δ 7.69 (d, J=2.0Hz, 1H), 7.21 (d, J=2.0Hz, 1H), 6.90 (s, 2H), 5.25-5.18 (m, 1H), 3.97-3.82 (m, 3H), 3.80-3.72 (m, 1H), 2.66 (s, 3H), 2.33-2.21 (m, 1H), 2.05-1.95 (m, 1H).
Step 3:(S)-N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (11) preparation
According to the method for step 3 in embodiment 1, by compound (J-11) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (11).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.67 (d, J=1.6Hz, 1H), 7.64-7.53 (m, 1H), 7.32 (d, J=1.6Hz, 1H), 7.22 (dt, J=8.6,2.3Hz, 1H), 6.84 (s, 2H), 5.43-5.29 (m, 1H), 4.00-3.85 (m, 3H), 3.83-3.73 (m, 1H), 3.65 (s, 3H), 2.75 (s, 3H), 2.35-2.22 (m, 1H), 2.12- 2.01 (m, 1H).
MS(ESI+)m/z 544.1[M+H]
+。
Embodiment 12:(S)-N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) Methanesulfomide (12)
According to the method for step 3 in embodiment 1, by compound (J-11) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (12).
1H NMR(400MHz,DMSO-d
6) δ 9.35 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.71 (d, J=1.8Hz, 1H), 7.34 (d, J=1.8Hz, 1H), 6.83 (s, 2H), 5.39-5.33 (m, 1H), 3.98 (s, 3H), 3.96-3.86 (m, 3H), 3.83-3.74 (m, 1H), 3.09 (s, 3H), 2.75 (s, 3H), 2.35-2.23 (m, 1H), 2.12-2.02 (m, 1H).
MS(ESI+)m/z 446.1[M+H]
+。
Embodiment 13:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (13)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline (I-13)
According to the method for step 1 in embodiment 1, by compound (H) and (tetrahydro -2H- pyrans -4- base) methanol prepare compound (I-13).
1H NMR(400MHz,DMSO-d
6) δ 8.02 (d, J=1.9Hz, 1H), 7.55 (d, J=1.9Hz, 1H), 5.85 (s, 2H), 4.07 (d, J=6.2Hz, 2H), 3.94-3.86 (m, 2H), 3.36 (dt, J=11.6,2.0Hz, 2H), 2.91 (s, 3H), 2.35 (s, 6H), 2.19-2.03 (m, 1H), 1.78-1.69 (m, 2H), 1.52-1.37 (m, 2H).
The preparation of the bromo- 4- methyl -8- of step 2:6- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -2- amine (J-13)
According to the method for step 2 in embodiment 1, by compound (I-13) prepare compound (J-13).
1H NMR(400MHz,DMSO-d
6) δ 7.65 (d, J=2.0Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 6.83 (s, 2H), 3.95 (d, J=6.7Hz, 2H), 3.92-3.84 (m, 2H), 3.40-3.32 (m, 2H), 2.65 (s, 3H), 2.14-1.99 (m, 1H), 1.78-1.69 (m, 2H), 1.43-1.28 (m, 2H).
The preparation of step 3:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (13)
According to the method for step 3 in embodiment 1, by compound (J-13) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (13).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.45 (d, J=2.1Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.64 (s, 1H), 7.63-7.55 (m, 1H), 7.34 (s, 1H), 7.22 (dt, J=8.6,2.4Hz, 1H), 6.79 (s, 2H), 4.05 (d, J=6.6Hz, 2H), 3.90 (dd, J=11.0,3.0 Hz, 2H), 3.64 (s, 3H), 3.37 (t, J=11.0Hz, 2H), 2.75 (s, 3H), 2.20-2.05 (m, 1H), 1.84 - 1.74 (m, 2H), 1.38 (qd, J=12.2,4.2Hz, 2H).
MS(ESI+)m/z 572.2[M+H]
+。
Embodiment 14:N- (5- (2- amino -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) Methanesulfomide (14)
According to the method for step 3 in embodiment 1, by compound (J-13) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (14).
1H NMR(400MHz,DMSO-d
6) δ 9.35 (s, 1H), 8.44 (d, J=2.2Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 7.67 (d, J=1.2Hz, 1H), 7.36 (d, J=1.2Hz, 1H), 6.77 (s, 2H), 4.06 (d, J=6.6Hz, 2H), 3.98 (s, 3H), 3.90 (dd, J=11.2,3.0Hz, 2H), 3.36 (t, J=10.9Hz, 2H), 3.08 (s, 3H), 2.75 (s, 3H), 2.20-2.04 (m, 1H), 1.77 (d, J=12.4Hz, 2H), 1.38 (qd, J=12.4,4.4Hz, 2H ).
MS(ESI+)m/z 474.2[M+H]
+。
Embodiment 15:N- (5- (2- amino -4- methyl -8- ((1- methyl piperidine -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (15)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((1- methyl piperidine -4- base) oxygroup) quinazoline (I-15)
According to the method for step 1 in embodiment 1, by compound (H) and 1- methyl piperidine -4- alcohol prepare compound (I-15)
1H NMR(400MHz,CDCl
3) δ 8.02 (d, J=2.0Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 5.86 (s, 2H), 4.88-4.73 (m, 1H), 2.91 (s, 3H), 2.64-2.54 (m, 2H), 2.37 (s, 6H), 2.35-2.25 (m, 2H), 2.18 (s, 3H), 2.04-1.89 (m, 2H), 1.87-1.71 (m, 2H).
The preparation of the bromo- 4- methyl -8- of step 2:6- ((1- methyl piperidine -4- base) oxygroup) quinazoline -2- amine (J-15)
According to the method for step 2 in embodiment 1, by compound (I-15) prepare compound (J-15).
1H NMR(400MHz,DMSO-d
6) δ 7.66 (d, J=2.0Hz, 1H), 7.28 (d, J=2.0Hz, 1H), 6.83 (s, 2H), 4.64-4.47 (m, 1H), 2.78-2.69 (m, 2H), 2.65 (s, 3H), 2.19 (s, 3H), 2.18-2.10 (m, 2H), 2.04-1.93 (m, 2H), 1.73-1.60 (m, 2H).
The preparation of step 3:N- (5- (2- amino -4- methyl -8- ((1- methyl piperidine -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (15)
According to the method for step 3 in embodiment 1, by compound (J-15) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (15).
1H NMR(400MHz,DMSO-d
6) δ 10.56 (br s, 1H), 8.40 (d, J=2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.71 (d, J=1.6Hz, 1H), 7.61-7.51 (m, 2H), 7.22 (dt, J=8.4,2.1Hz, 1H), 6.84 (s, 2H), 4.95-4.85 (m, 1H), 3.64 (s, 3H), 3.10-2.95 (m, 2H), 2.76 (s, 3H), 2.69 (s, 3H), 2.25-2.13 (m, 2H), 2.07-1.95 (m, 2H).
MS(ESI+)m/z 571.18994[M+H]
+。
Embodiment 16:N- (5- (2- amino -4- methyl -8- ((2- morpholine base oxethyl) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (16)
The preparation of step 1:4- (2- ((the bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin -8- base) oxygroup) ethyl) morpholine (I-16)
According to the method for step 1 in embodiment 1, by compound (H) and 2- morpholinyl ethyl alcohol prepare compound (I-16).
1H NMR(400MHz,CDCl
3) δ 8.02 (d, J=2.0Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 5.85 (s, 2H), 4.33 (t, J=5.1Hz, 2H), 4.04 (q, J=7.0Hz, 4H), 3.64-3.46 (m, 4H), 2.92 (s, 3H), 2.81 (t, J=5.1Hz, 2H), 2.53 (s, 6H).
The preparation of the bromo- 4- methyl -8- of step 2:6- (2- morpholine base oxethyl) quinazoline -2- amine (J-16)
According to the method for step 2 in embodiment 1, by compound (I-16) prepare compound (J-16).
1H NMR(500MHz,DMSO-d
6) δ 7.67 (s, 1H), 7.28 (s, 1H), 6.90 (s, 2H), 4.21 (t, J=5.9Hz, 2H), 3.67-3.50 (m, 4H), 2.74 (t, J=5.8Hz, 2H), 2.66 (s, 3H), 2.51 (br s, 4H).
Step 3:N- (the preparation of 5- (2- amino -4- methyl -8- ((2- morpholine base oxethyl) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (16)
According to the method for step 3 in embodiment 1, by compound (J-16) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (16).
1H NMR(400MHz,DMSO-d
6) δ 8.44 (d, J=2.2Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 7.58 (ddd, J=10.4,9.4,2.4Hz, 1H), 7.38 (d, J=1.6Hz, 1H), 7.26-7.17 (m, 1H), 6.84 (s, 2H), 4.31 (t, J=6.0Hz, 2H), 3.64 (s, 3H), 3.61 (t, J=4.6Hz, 4H), 2.81 (t, J=6.0Hz, 2H), 2.75 (s, 3H), 2.61-2.52 (m, 4H).
MS(ESI+)m/z 587.2[M+H]
+。
Embodiment 17:N- (5- (2- amino -8- ((4,4- difiuorocyclohexyl) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (17)
The preparation of the bromo- 8- of step 1:6- ((4,4- difiuorocyclohexyl) oxygroup) -2- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin (I-17)
According to the method for step 1 in embodiment 1, by compound (H) and 4,4- difluorocyclohex alcohol prepare compound (I-17).
1H NMR(400MHz,CDCl
3) δ 7.82 (d, J=1.8Hz, 1H), 7.31 (d, J=1.8Hz, 1H), 5.92 (s, 2H), 4.85-4.77 (m, 1H), 2.91 (s, 3H), 2.45 (s, 6H), 2.28-2.14 (m, 4H), 2.07-1.92 (m, 4H).
The preparation of the bromo- 8- of step 2:6- ((4,4- difiuorocyclohexyl) oxygroup) -4- methylquinazolin -2- amine (J-17)
According to the method for step 2 in embodiment 1, by compound (I-17) prepare compound (J-17).
1H NMR(400MHz,CDCl
3) δ 7.65 (d, J=1.6Hz, 1H), 7.20 (d, J=1.6Hz, 1H), 5.28 (br s, 2H), 4.71-4.62 (m, 1H), 2.74 (s, 3H), 2.41-2.23 (m, 2H), 2.23-2.10 (m, 2H), 2.07-1.86 (m, 4H)
The preparation of step 3:N- (5- (2- amino -8- ((4,4- difiuorocyclohexyl) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (17)
According to the method for step 3 in embodiment 1, by compound (J-17) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (17).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.76 (dt, J=8.4,6.6Hz, 1H), 7.69 (d, J=1.4Hz, 1H), 7.63-7.54 (m, 1H), 7.50 (d, J=1.4Hz, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 6.76 (s, 2H), 4.97-4.88 (m, 1H), 3.64 (s, 3H), 2.76 (s, 3H), 2.28-2.11 (m, 2H), 2.08-1.81 (m, 6H).
MS(ESI+)m/z 592.2[M+H]
+。
Embodiment 18:N- (5- (2- amino -8- ((4- methoxycyclohexyl) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (18)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -8- ((4- methoxycyclohexyl) oxygroup) -4- methylquinazolin (I-18)
According to the method for step 1 in embodiment 1, by compound (H) and 4- methoxycyclohexyl -1- alcohol prepare compound (I-18).
1H NMR(400MHz,CDCl
3) δ 8.01 (d, J=1.9Hz, 1H), 8.00 (d, J=1.9Hz, 1H), 7.64 (d, J=1.9Hz, 1H), 7.62 (d, J=1.8Hz, 1H), 5.85 (s, 2H), 4.86-4.74 (m, 2H), 3.36-3.26 (m, 2H), 3.25 (s, 3H), 3.24 (s, 3H), 2.91 (s, 6H), 2.36 (s, 6H), 2.35 (s, 6H), 2.08-1.84 (m, 6H), 1.76-1.68 (m, 6H), 1.65-1.54 (m, 2H), 1.53-1.42 (m, 2H).
The bromo- 8- of step 2:6- ((4- methoxycyclohexyl) oxygroup) -4- methylquinazolin -2- amine (J-18)
According to the method for step 2 in embodiment 1, by compound (I-18) prepare compound (J-18).Obtain new point similar in two polarity.
The lesser point of polarity:
1H NMR(400MHz,DMSO-d
6) δ 7.65 (d, J=1.8Hz, 1H), 7.29 (d, J=1.8Hz, 1H), 6.82 (s, 2H), 4.62-4.52 (m, 1H), 3.29-3.20 (m, 4H), 2.65 (s, 3H), 2.08-1.95 (m, 4H), 1.57-1.30 (m, 4H).
MS(ESI+)m/z 366.1[M+H]
+。
The biggish point of polarity:
1H NMR(400MHz,DMSO-d
6) δ 7.65 (d, J=2.0Hz, 1H), 7.27 (d, J=2.0Hz, 1H), 6.80 (s, 2H), 4.71-4.54 (m, 1H), 3.36-3.32 (m, 1H), 3.24 (s, 3H), 2.65 (s, 3H), 1.86-1.54 (m, 8H).
MS(ESI+)m/z 366.1[M+H]
+。
Step 3:N- (5- (2- amino -8- ((4- methoxycyclohexyl) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (18)
Compound 18-1: it according to the method for step 3 in embodiment 1, is prepared by the lesser product point of polarity in step 2.
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 7.95 (d, J=2.2Hz, 1H), 7.75 (dt, J=8.6,6.4Hz, 1H), 7.64 (s, 1H), 7.62-7.55 (m, 1H), 7.41 (s, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 6.77 (s, 2H), 4.76-4.65 (m, 1H), 3.64 (s, 3H), 3.28-3.22 (m, 4H), 2.75 (s, 3H), 2.12-1.30 (m, 4H), 1.60-1.30 (m, 4H).
MS(ESI+)m/z 586.2[M+H]
+.Compound 18-2: it according to the method for step 3 in embodiment 1, is prepared by the biggish product point of polarity in step 2.
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.42 (d, J=2.2Hz, 1H), 7.93 (d, J=2.2Hz, 1H), 7.76 (dt, J=8.4,6.4Hz, 1H), 7.64 (s, 1H), 7.63-7.54 (m, 1H), 7.38 (s, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 6.74 (s, 2H), 4.83-4.67 (m, 1H), (3.65 s, 3H), 3.38-3.28 (m, 1H), 3.25 (s, 3H), (2.75 s, 3H), 1.88-1.70 (m, 6H), 1.69-1.55 (m, 2H).
MS(ESI+)m/z 586.2[M+H]
+。
Embodiment 19:N- (5- (2- amino -8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (19)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin (I-19)
According to the method for step 1 in embodiment 1, by compound (H) and 2,2- dimethyl tetrahydro -2H- pyrans -4- alcohol prepare compound (I-19).
1H NMR(400MHz,CDCl
3) δ 7.81 (d, J=1.9Hz, 1H), 7.29 (d, J=1.9Hz, 1H), 4.85-4.76 (m, 1H), 4.03-3.95 (m, 1H), 3.80-3.70 (m, 1H), 2.91 (s, 3H), 2.44 (s, 6H), 2.17-2.08 (m, 1H), 2.08-1.99 (m, 1H), 1.92-1.75 (m, 2H), 1.34 (s, 3H), 1.28 (s, 3H).The preparation of the bromo- 8- of step 2:6- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin -2- amine (J-19)
According to the method for step 2 in embodiment 1, by compound (I-19) prepare compound (J-19).
1H NMR(500MHz,DMSO-d
6) δ 7.67 (d, J=1.5Hz, 1H), 7.36 (d, J=1.5Hz, 1H), 6.83 (s, 2H), 4.95-4.84 (m, 1H), 3.80-3.61 (m, 2H), 2.66 (s, 3H), 2.06-1.94 (m, 2H), 1.54-1.39 (m, 2H), 1.24 (s, 3H), 1.21 (s, 3H).
Step 3:N- (5- (2- amino -8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (19) preparation
According to the method for step 3 in embodiment 1, by compound (J-19) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (19).
1H NMR(400MHz,DMSO-d
6) δ 10.29 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 7.96 (d, J=2.3Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 7.63-7.54 (m, 1H), 7.44 (d, J=1.6Hz, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 6.78 (s, 2H), 5.08-4.93 (m, 1H), 3.82-3.66 (m, 2H), 3.65 (s, 3H), 2.75 (s, 3H), 2.13-1.93 (m, 2H), 1.59-1.41 (m, 2H), 1.25 ( S, 3H), 1.22 (s, 3H).
MS(ESI+)m/z 586.2[M+H]
+。
Embodiment 20:N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -2- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (20)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((tetrahydrofuran -2- base) methoxyl group) quinazoline (I-20)
According to the method for step 1 in embodiment 1, by compound (H) and tetrahydrofurfuryl alcohol prepare compound (I-20).
1H NMR(400MHz,DMSO-d
6) δ 8.03 (d, J=1.8Hz, 1H), 7.58 (d, J=1.8Hz, 1H), 5.85 (s, 2H), 4.32-4.14 (m, 3H), 3.86-3.77 (m, 1H), 3.74-3.66 (m, 1H), 2.92 (s, 3H), 2.34 (s, 6H), 2.10-1.91 (m, 2H), 1.90-1.77 (m, 2H).
The preparation of the bromo- 4- methyl -8- of step 2:6- ((tetrahydrofuran -2- base) methoxyl group) quinazoline -2- amine (J-20)
According to the method for step 2 in embodiment 1, by compound (I-20) prepare compound (J-20).
1H NMR(400MHz,DMSO-d
6) δ 7.66 (d, J=2.0Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 6.91 (s, 2H), 4.28-4.18 (m, 1H), 4.11-3.98 (m, 2H), 3.87-3.75 (m, 1H), 3.6673-3.66 (m, 1H), 2.66 (s, 3H), 2.08-1.97 (m, 1H), 1.97-1.77 (m, 2H), 1.74-1.62 (m, 1H).
The preparation of step 3:N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -2- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (20)
According to the method for step 3 in embodiment 1, by compound (J-20) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (20).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.45 (d, J=2.3Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 7.63-7.55 (m, 1H), 7.37 (d, J=1.6Hz, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 6.85 (s, 2H), 4.32-4.22 (m, 1H), 4.20-4.08 (m, 2H), 3.87-3.79 (m, 1H), 3.71 (dt, J=7.6,6.4Hz, 1H), 3.64 (s, 3H), 2.75 (s, 3 ), H 2.11-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.78-1.67 (m, 1H).
MS(ESI+)m/z 558.2[M+H]
+。
Embodiment 21:N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (21)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methyl -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline (I-21)
According to the method for step 1 in embodiment 1, by compound (H) and (tetrahydrofuran -3- base) methanol prepare compound (I-21).
1H NMR(400MHz,DMSO-d
6) δ 8.03 (d, J=1.6Hz, 1H), 7.58 (d, J=1.6Hz, 1H), 5.85 (s, 2H), 4.23-4.08 (m, 2H), 3.88-3.75 (m, 2H), 3.69 (dd, J=14.8,7.6Hz, 1H), 3.62 (dd, J=8.6,5.6Hz, 1H), 2.92 (s, 3H), 2.84-2.71 (m, 1H), 2.35 (s, 6H), 2.12-2.00 (m, 1H), 1.81-1.70 (m, 1H).
The preparation of the bromo- 4- methyl -8- of step 2:6- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -2- amine (J-21)
According to the method for step 2 in embodiment 1, by compound (I-21) prepare compound (J-21).
1H NMR(400MHz,DMSO-d
6) δ 7.67 (d, J=2.0Hz, 1H), 7.26 (d, J=2.0Hz, 1H), 6.86 (s, 2H), 4.08-3.95 (m, 2H), 3.84-3.74 (m, 2H), 3.67 (dt, J=8.0,6.6Hz, 1H), 3.59 (dd, J=8.6,5.0Hz, 1H), 2.78-2.68 (m, 1H), 2.66 (s, 3H), 2.09-1.98 (m, 1H), 1.75-1.65 (m, 1H).
The preparation of step 3:N- (5- (2- amino -4- methyl -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (21)
According to the method for step 3 in embodiment 1, by compound (J-21) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (21).
1H NMR(400MHz,DMSO-d
6) δ 10.27 (s, 1H), 8.45 (d, J=2.2Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 7.75 (dt, J=8.4,6.4Hz, 1H), 7.66 (d, J=1.2Hz, 1H), 7.63-7.54 (m, 1H), 7.38 (d, J=1.2Hz, 1H), 7.21 (dt, J=8.4,2.2Hz, 1H), 6.80 (s, 2H), 4.19-4.03 (m, 2H), 3.85-3.77 (m, 2H), 3.73-3.60 (m, 5H), 2.85-2.70 (m, 4H), 2.12-1.99 (m, 1H), 1.79-1.69 (m , 1H).
MS(ESI+)m/z 558.2[M+H]
+。
Embodiment 22:N- (5- (2- amino -8- (cyclohexyl oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (22)
The preparation of the bromo- 8- of step 1:6- (cyclohexyl oxygroup) -2- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin (I-22)
By compound (H) (1.661g, 5mmol) in seal pipe, the reaction mixture of cyclohexyl bromide (8.15g, 50mmol) and potassium carbonate (6.91g, 50mmol) in acetonitrile (40mL) is refluxed overnight.After the mixture of generation is cooled to room temperature, filtering.Silica gel (5g) is added into filtrate, by evaporated under reduced pressure in the mixture of generation.It is yellow oil (1.7g, yield 82%) that residue, which obtains product (I-22) through flash column chromatography (silica gel, PE/EtOAc=100:1, v/v) purifying,.
1H NMR(500MHz,DMSO-d
6) δ 8.00 (d, J=2.0Hz, 1H), 7.61 (d, J=2.0Hz, 1H), 5.85 (s, 2H), 4.79-4.72 (m, 1H), 2.91 (s, 3H), 2.35 (s, 6H), 1.95-1.86 (m, 2H), 1.79-1.70 (m, 2H), 1.69-1.57 (m, 2H), 1.56-1.31 (m, 4H).
The preparation of the bromo- 8- of step 2:6- (cyclohexyl oxygroup) -4- methylquinazolin -2- amine (J-22)
According to the method for step 2 in embodiment 1, by compound (I-22) prepare compound (J-22).
1H NMR(400MHz,DMSO-d
6) δ 7.64 (d, J=2.0Hz, 1H), 7.25 (d, J=2.0Hz, 1H), 6.83 (s, 2H), 4.58-4.45 (m, 1H), 2.65 (s, 3H), 2.04-1.95 (m, 2H), 1.82-1.67 (m, 2H), 1.65-1.27 (m, 6H).
The preparation of step 3:N- (5- (2- amino -8- (cyclohexyl oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (22)
According to the method for step 3 in embodiment 1, by compound (J-22) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (22).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.42 (d, J=2.3Hz, 1H), 7.93 (d, J=2.3Hz, 1H), 7.76 (dt, J=8.4,6.4Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.62-7.56 (m, 1H), 7.36 (d, J=1.4Hz, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 6.76 (s, 2H), 4.70-4.60 (m, 1H), 3.65 (s, 3H), 2.74 (s, 3H), 2.09-1.97 (m, 2H), 1.85-1.71 (m, 2H), 1.66-1.30 (m, 6H).
MS(ESI+)m/z 556.2[M+H]
+。
Embodiment 23:N- (5- (2- amino -8- (cyclopentyloxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (23)
The preparation of step 1:6- bromo- 8- (cyclopentyloxy) -2- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin (I-23)
According to the method for step 1 in embodiment 22, by compound (H) and cyclopentyl bromide prepare compound (I-23).
1H NMR(500MHz,DMSO-d
6) δ 8.00 (d, J=1.5Hz, 1H), 7.53 (d, J=1.5Hz, 1H), 5.85 (s, 2H), 5.18-5.09 (m, 1H), 2.91 (s, 3H), 2.34 (s, 6H), 2.03-1.92 (m, 2H), 1.89-1.80 (m, 2H), 1.80-1.70 (m, 2H), 1.69-1.58 (m, 2H).
The preparation of step 2:6- bromo- 8- (cyclopentyloxy) -4- methylquinazolin -2- amine (J-23)
According to the method for step 2 in embodiment 1, by compound (I-23) prepare compound (J-23).
1H NMR(400MHz,DMSO-d
6) δ 7.64 (d, J=2.0Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.83 (s, 2H), 5.00-4.94 (m, 1H), 2.65 (s, 3H), 2.04-1.91 (m, 2H), 1.80-1.68 (m, 4H), 1.66-1.53 (m, 2H).
The preparation of step 3:N- (5- (2- amino -8- (cyclopentyloxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (23)
According to the method for step 3 in embodiment 1, by compound (J-23) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (23).
1H NMR(400MHz,DMSO-d
6) δ 10.30 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.93 (d, J=2.4Hz, 1H), 7.77 (dt, J=8.4,6.4Hz, 1H), 7.63 (d, J=1.8Hz, 1H), 7.63-7.56 (m, 1H), 7.27 (d, J=1.6Hz, 1H), 7.22 (dt, J=8.4,2.2Hz, 1H), 6.79 (s, 2H), 5.14-5.08 (m, 1H), 3.66 (s, 3H), 2.75 (s, 3H), 2.10-1.93 (m, 2H), 1.88-1.69 (m, 4H), 1.69-1.51 (m, 2H).
MS(ESI+)m/z 542.2[M+H]
+。
Embodiment 24:N- (5- (2- amino -8- cyclobutoxy group -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (24)
The preparation of the bromo- 8- cyclobutoxy group -2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin (I-24)
According to the method for step 1 in embodiment 22, by compound (H) and cyclobutyl bromine prepare compound (I-24).
1H NMR(400MHz,DMSO-d
6) δ 8.02 (d, J=1.9Hz, 1H), 7.35 (d, J=1.9Hz, 1H), 5.85 (s, 2H), 4.98 (p, J=7.0Hz, 1H), 2.91 (s, 3H), 2.60-2.51 (m, 2H), 2.33 (s, 6H), 2.19-2.05 (m, 2H), 1.92-1.77 (m, 1H), 1.77-1.64 (m, 1H).
The preparation of the bromo- 8- cyclobutoxy group -4- methylquinazolin -2- amine (J-24) of step 2:6-
According to the method for step 2 in embodiment 1, by compound (I-24) prepare compound (J-24).
1H NMR(400MHz,DMSO-d
6) δ 7.65 (d, J=2.0Hz, 1H), 7.00 (d, J=2.0Hz, 1H), 6.89 (s, 2H), 4.81 (p, J=7.0Hz, 1H), 2.65 (s, 3H), 2.49-2.42 (m, 2H), 2.16-2.00 (m, 2H), 1.89-1.57 (m, 2H)
The preparation of step 3:N- (5- (2- amino -8- cyclobutoxy group -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (24)
According to the method for step 3 in embodiment 1, by compound (J-24) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (24).
1H NMR(400MHz,DMSO-d
6) δ 10.30 (s, 1H), 8.42 (d, J=2.3Hz, 1H), 7.92 (d, J=2.3Hz, 1H), 7.77 (dt, J=8.6,6.4Hz, 1H), 7.64 (d, J=1.6Hz, 1H), 7.63-7.55 (m, 1H), 7.23 (dt, J=8.6,2.4Hz, 1H), (7.12 d, J=1.6Hz, 1H), 6.84 (s, 2H), 4.94 (p, J=7.2Hz, 1H), 3.66 (s, 3H), 2.75 (s, 3H), 2.55-2.46 (m, 2H), 2.19-2.06 (m, 2H), 1.89-1.62 (m, 2H).
MS(ESI+)m/z 528.1[M+H]
+。
The preparation of embodiment 25:N- (5- (2- amino -8- (2- methoxyethoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (25)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -8- (2- methoxyethoxy) -4- methylquinazolin (I-25)
According to the method for step 1 in embodiment 22, by compound (H) and 2- chloroethyl methyl ether prepare compound (I-25).
1H NMR(400MHz,DMSO-d
6) δ 7.80 (d, J=1.9Hz, 1H), 7.31 (d, J=1.9Hz, 1H), 5.90 (s, 2H), 4.33 (t J=4.8Hz, 2H), 3.90 (t, J=4.8Hz, 3H), (3.48 s, 3H), 2.91 (s, 3H), 2.43 (s, 6H).
The preparation of the bromo- 8- of step 2:6- (2- methoxyethoxy) -4- methylquinazolin -2- amine (J-25)
According to the method for step 2 in embodiment 1, by compound (I-25) prepare compound (J-25).
1H NMR(400MHz,DMSO-d
6) δ 7.67 (d, J=1.8Hz, 1H), 7.23 (d, J=1.8Hz, 1H), 6.90 (s, 2H), 4.21 (t, J=4.4Hz, 2H), 3.90 (t, J=4.4Hz, 3H), 3.32 (s, 3H), 2.66 (s, 3H).
The preparation of step 3:N- (5- (2- amino -8- (2- methoxyethoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (25)
According to the method for step 3 in embodiment 1, by compound (J-25) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (25).
1H NMR(400MHz,DMSO-d
6) δ 10.32 (br s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.76 (dt, J=8.5,6.6Hz, 1H), 7.64 (d, J=1.4Hz, 1H), 7.63-7.55 (m, 1H), 7.34 (d, J=1.4Hz, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 6.87 (s, 2H), 4.35-4.28 (m, 2H), 3.79-3.73 (m, 2H), 3.64 (s, 3H), 3.35 (s, 3H), 2.75 (s, 3H).
MS(ESI+)m/z 532.1[M+H]
+。
Embodiment 26:N- (5- (2- amino -8- isopropoxy -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (26)
The preparation of the bromo- 2- of step 1:6- (2,5- dimethyl -1H- pyrroles -1- base) -8- isopropoxy -4- methylquinazolin (I-26)
According to the method for step 1 in embodiment 22, by compound (H) and isopropyl bromide prepare compound (I-26).
1H NMR(400MHz,DMSO-d
6) δ 8.02 (d, J=1.8Hz, 1H), 7.59 (d, J=1.8Hz, 1H), 5.85 (s, 2H), 4.98-4.88 (m, 1H), 2.92 (s, 3H), 2.34 (s, 6H), 1.36 (d, J=6.0Hz, 6H).
The preparation of the bromo- 8- isopropoxy -4- methylquinazolin -2- amine (J-26) of step 2:6-
According to the method for step 2 in embodiment 22, by compound (I-26) prepare compound (J-26).
1H NMR(400MHz,DMSO-d
6) δ 7.64 (d, J=2.0Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 6.84 (s, 2H), 4.86-4.75 (m, 1H), 2.65 (s, 3H), 1.31 (d, J=6.0Hz, 6H).
The preparation of step 3:N- (5- (2- amino -8- isopropoxy -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (26)
According to the method for step 3 in embodiment 1, by compound (J-26) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (26).
1H NMR(400MHz,DMSO-d
6) δ 10.30 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 7.94 (d, J=2.3Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.64 (d, J=1.6Hz, 1H), 7.63-7.56 (m, 1H), 7.33 (s, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 6.83 (s, 2H), 5.00-4.89 (m, 1H), 3.64 (s, 3H), 2.75 (s, 3H), 1.34 (d, J=6.0Hz, 6H).
MS(ESI+)m/z 516.1[M+H]
+。
Embodiment 27:N- (5- (2- amino -8- (cyclo propyl methoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (27)
The preparation of step 1:6- bromo- 8- (cyclo propyl methoxy) -2- (2,5- dimethyl -1H- pyrroles -1- base) -4- methylquinazolin (I-27)
According to the method for step 1 in embodiment 22, by compound (H) and cyclopropyl methyl bromide prepare compound (I-27).
1H NMR(400MHz,DMSO-d
6) δ 7.64 (d, J=1.8Hz, 1H), 7.14 (d, J=1.8Hz, 1H), 6.91 (s, 2H), 3.90 (d, J=7.2Hz, 2H), 2.65 (s, 3H), 1.33-1.23 (m, 1H), 0.65-0.55 (m, 2H), 0.35 (q, J=4.8Hz, 2H).
The preparation of step 2:6- bromo- 8- (cyclo propyl methoxy) -4- methylquinazolin -2- amine (J-27)
According to the method for step 2 in embodiment 22, by compound (I-27) prepare compound (J-27).
1H NMR(400MHz,DMSO-d
6) δ 7.64 (d, J=1.8Hz, 1H), 7.14 (d, J=1.8Hz, 1H), 6.91 (s, 2H), 3.90 (d, J=7.2Hz, 2H), 2.65 (s, 3H), 1.33-1.23 (m, 1H), 0.65-0.55 (m, 2H), 0.35 (q, J=4.8Hz, 2H).
The preparation of step 3:N- (5- (2- amino -8- (cyclo propyl methoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (27)
According to the method for the method of step 3 in embodiment 1, by compound (J-27) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (27).
1H NMR(400MHz,DMSO-d
6) δ 10.27 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 7.94 (d, J=2.2Hz, 1H), 7.75 (dt, J=8.6,6.4Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.62-7.55 (m, 1H), 7.27 (d, J=1.6Hz, 1H), 7.24-7.18 (m, 1H), 6.85 (br s, 2H), 4.00 (d, J=7.0Hz, 2H), 3.63 (s, 3H), 2.75 (s, 3H), 1.37-1.27 (m, 1H), 0.67-0.57 (m, 2H), 0.40-0.33 (m, 2H).
MS(ESI+)m/z 528.1[M+H]
+。
The preparation of embodiment 28:N- (5- (2- amino -8- methoxyl group -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (28)
According to the method for step 3 in embodiment 1, by compound (F) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (28).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.46 (d, J=2.4Hz, 1H), 7.97 (d, J=2.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), (7.65 d, J=1.7Hz, 1H), 7.63-7.55 (m, 1H), 7.31 (d, J=1.7Hz, 1H), 7.26-7.18 (m, 1H), 6.83 (s, 2H), 3.95 (s, 3H), 3.64 (s, 3H), 2.76 (s, 3H).
MS(ESI+)m/z 488.1[M+H]
+。
Embodiment 29:N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (29)
The preparation of the bromo- N of step 1:6-, 4- dimethyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- amine (K-1)
Sodium hydrogen (60% is scattered in mineral oil, 153mg, 3.82mmol) is added to compound (J-1) (517mg) in the solution of DMF (50mL) at 0 DEG C.The reaction mixture of generation is stirred into 30min at 0 DEG C, iodomethane (217mg, 1.53mmol) then is added.The reaction mixture of generation is stirred at room temperature 3 hours.Reaction mixture is released with water (250mL), is neutralized with 2M hydrochloric acid, is extracted with ethyl acetate (50mL × 3).The organic layer merged is washed with water (50mL × 2) and saline solution (50mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow solid (113mg, 21%) that residue, which obtains product (K-1) through flash chromatography column (silica gel, DCM/EtOAc=4:1) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 7.74 (d, J=1.8Hz, 1H), 7.39 (d, J=1.8Hz, 1H), 7.34 (q, J=4.8Hz, 1H), 4.94-4.76 (m, 1H), 3.99-3.82 (m, 2H), 3.53-3.43 (m, 2H), 2.88 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.06-1.88 (m, 2H), 1.77-1.57 (m, 2H).
Step 2:N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (29)
By compound (K-1) (35mg, 0.1mmol), N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide (51mg, 0.12mmol) and 2M wet chemical (0.15mL, 0.63mmol) are in 1, mixture degassing in 4- dioxane (7mL), is then added PdCl
2(dppf) (8mg, 0.01mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with ethyl acetate (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is separated, (30mL × 2) water layer is extracted with ethyl acetate.The organic layer merged is washed with water (50mL) and saline solution (50mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow solid (40mg, yield 70%) that residue, which is prepared thin-layer chromatography (silica gel, methylene chloride/methanol=20:1, v/v) purifying and obtains product (29),.
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.42 (d, J=2.0Hz, 1H), 7.93 (d, J=2.0Hz, 1H), 7.83-7.66 (m, 2H), 7.63-7.53 (m, 1H), 7.50 (s, 1H), 7.28 (q, J=4.0Hz, 1H), 7.21 (dt, J=8.4,2.0Hz, 1H), 4.97-4.88 (m 1H), 4.01-3.88 (m, 2H), 3.64 (s, 3H), 3.53-3.44 (m, 2H), 2.91 (d, J=4.4Hz, 3H), 2.76 (s, 3H), 2.08-1.90 (m, 2H), 1.81-1.63 (m, 2 H).
MS(ESI+)m/z 572.2[M+H]
+。
Embodiment 30:N- (5- (2- (ethylamino) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (30)
The preparation of the bromo- N- ethyl -4- methyl -8- of step 1:6- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- amine (K-2)
According to the method for step 1 in embodiment 29, by compound (J-1) and iodoethane prepare compound (K-2).
1H NMR(400MHz,DMSO-d
6) δ 7.73 (d, J=1.6Hz, 1H), 7.41 (br s, 1H), 7.38 (d, J=1.6Hz, 1H), 4.90-4.78 (m, 1H), 3.98-3.82 (m, 2H), 3.52-3.43 (m, 2H), 3.43-3.33 (m, 2H), 2.66 (s, 3H), 2.02-1.90 (m, 2H), 1.73-1.61 (m, 2H), 1.17 (t, J=7.2Hz, 3H).
The preparation of step 2:N- (5- (2- (ethylamino) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (30)
According to the method for step 2 in embodiment 29, by compound (K-2) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (30).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.42 (d, J=2.1Hz, 1H), 7.93 (d, J=2.3Hz, 1H), 7.80-7.69 (m, 2H), 7.59 (ddd, J=10.4,9.6,2.4Hz, 1H), 7.49 (d, J=1.2Hz, 1H), 7.35 (t, J=5.0Hz, 1H), 7.26-7.16 (m, 1H), 4.95-4.87 (m, 1H), 3.98-3.89 (m, 2H), 3.64 (s, 3H), 3.52-3.36 (m, 4H), 2.75 (s, 3H), 2.05-1.92 (m, 2H), 1.80-1.63 (m, 2H), 1. 19 (t, J=7.1Hz, 3H).
MS(ESI+)m/z 586.2[M+H]
+。
Embodiment 31:N- (5- (2- ((cyclopropyl methyl) amino) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (31)
The preparation of the bromo- N- of step 1:6- (cyclopropyl methyl) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- amine (K-3)
According to the method for step 1 in embodiment 29, by compound (J-1) and cyclopropyl methyl bromide prepare compound (K-3).
1H NMR(400MHz,DMSO-d
6) δ 7.73 (s, 1H), 7.51 (br s, 1H), 7.37 (d, J=1.7Hz, 1H), 4.88-4.78 (m, 1H), 3.95-3.83 (m, 2H), 3.55-3.39 (m, 2H), 3.24 (t, J=6.3Hz, 2H), 2.66 (s, 3H), 2.03-1.91 (m, 2H), 1.74-1.59 (m, 2H), 1.15-1.06 (m, 1H), 0.45-0.35 (m, 2H), 0.27 (q, J=4.4Hz, 2H).
The preparation of step 2:N- (5- (2- ((cyclopropyl methyl) amino) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (31)
According to the method for step 2 in embodiment 29, by compound (K-3) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (31).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.80-7.70 (m, 2H), 7.63-7.55 (m, 1H), 7.48 (d, J=1.2Hz, 1H), 7.45 (br s, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 4.96-4.86 (m, 1H), 4.00-3.89 (m, 2H), (3.64 s, 3H), 3.54-3.42 (m, 2H), 3.28 (t, J=6.4Hz, 2H), 2.76 (s, 3H), 2.06-1.94 (m, 2H), 1.80-1.63 ( M, 2H), 1.21-1.05 (m, 1H), 0.50-0.38 (m, 2H), 0.29 (q, J=4.8Hz, 2H).
MS(ESI+)m/z 612.2[M+H]
+。
Embodiment 32:(R)-N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (32)
Step 1:(R) the bromo- N of -6-, 4- dimethyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -2- amine (K-4)
According to the method for step 1 in embodiment 29, by compound (J-9) prepare compound (K-4).
1H NMR(400MHz,DMSO-d
6) δ 7.72 (d, J=2.0Hz, 1H), 7.34 (q, J=4.8Hz, 1H), 7.25 (s, 1H), 5.32-5.22 (m, 1H), 3.96-3.86 (m, 3H), 3.81-3.73 (m, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.28-2.15 (m, 1H), 2.11-1.98 (m, 1H).
Step 4:(R)-N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (32)
According to the method for step 2 in embodiment 29, by compound (K-4) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (32).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.44 (d, J=2.2Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.80-7.70 (m, 2H), 7.63-7.54 (m, 1H), 7.38 (s, 1H), 7.29 (q, J=4.8Hz, 1H), 7.25-7.17 (m, 1H), 5.43-5.36 (m, 1H), 4.00-3.89 (m, 3H), 3.83-3.76 (m, 1H), 3.64 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.76 (s, 3H), 2.28-2.15 (m, 1H), 2.15-2.02 (m, 1H).
MS(ESI+)m/z 558.2[M+H]
+。
Embodiment 33:(R)-N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2- chlorine 4- fluorobenzenesulfonamide (33)
According to the method for step 1 in embodiment 29, by compound (K-4) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) the chloro- 4- fluorobenzenesulfonamide prepare compound (33) of -2-.
1H NMR(400MHz,DMSO-d
6) δ 10.17 (s, 1H), 8.42 (d, J=2.4Hz, 1H), 7.94 (dd, J=8.8,6.0Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.76 (dd, J=8.8,2.6Hz, 1H), 7.69 (d, J=1.6Hz, 1H), 7.40-7.32 (m, 2H), 7.29 (q, J=4.8Hz, 1H), 5.42-5.35 (m, 1H), 4.00-3.89 (m, 3H), 3.79 (dt, J=8.0,4.4Hz, 1H), 3.66 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.28- 2.15 (m, 1H), 2.14-2.04 (m, 1H)
MS(ESI+)m/z 574.1[M+H]
+。
Embodiment 34:(R)-N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide (34)
According to the method for step 2 in embodiment 29, by compound (K-4) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide prepare compound (34).
1H NMR(400MHz,DMSO-d
6) δ 10.33 (s, 1H), 8.48 (d, J=2.4Hz, 1H), 7.96 (d, J=2.4Hz, 1H), 7.73 (d, J=1.6Hz, 1H), 7.42-7.38 (m, 2H), 7.29 (t, J=4.8Hz, 1H), 7.25 (d, J=4.4Hz, 1H), 5.43-5.36 (m, 1H), 4.00-3.90 (m, 3H), 3.80 (dt, J=8.0,4.4Hz, 1H), 3.75 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.77 (s, 3H), 2.30-2.16 (m, 1H), 2.15-2.05 (m, 1H).
Embodiment 35:(S)-N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (35)
Step 1:(S) the bromo- N of -6-, the preparation of 4- dimethyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -2- amine (K-7)
According to the method for step 1 in embodiment 29, by compound (J-11) prepare compound (K-7).
1H NMR(400MHz,DMSO-d
6) δ 7.72 (d, J=2.0Hz, 1H), 7.34 (q, J=4.8Hz, 1H), 7.25 (s, 1H), 5.32-5.22 (m, 1H), 3.96-3.86 (m, 3H), 3.77 (dt, J=8.2,4.6Hz, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.27-2.17 (m, 1H), 2.09-1.99 (m, 1H).
Step 2:(S)-N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (35) preparation
According to the method for step 2 in embodiment 29, by compound (K-7) prepare compound (35).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.44 (d, J=2.4Hz, 1H), 7.97 (d, J=2.4Hz, 1H), 7.80-7.70 (m, 2H), 7.59 (ddd, J=10.4,9.2,2.4Hz, 1H), 7.38 (s, 1H), 7.29 (q, J=4.8Hz, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 5.43-5.36 (m, 1H), 4.03-3.87 (m, 3H), 3.79 (dt, J=8.2,4.6Hz, 1H), 3.64 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.76 (s, 3H), 2.28-2. 16 (m, 1H), 2.15-2.04 (m, 1H).
MS(ESI+)m/z 558.2[M+H]
+。
Embodiment 36:N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (36)
The preparation of the bromo- N of step 1:6-, 4- dimethyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -2- amine (K-8)
According to the method for step 1 in embodiment 29, by compound (J-13) prepare compound (K-8).
1H NMR(400MHz,DMSO-d
6) δ 7.66 (d, J=2.0Hz, 1H), 7.28 (q, J=4.8Hz, 1H), 7.24 (d, J=1.4Hz, 1H), 3.98 (d, J=6.8Hz, 2H), 3.94-3.84 (m, 2H), 3.35 (dt, J=11.6,2.0Hz, 2H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.16-2.02 (m, 1H), 1.80-1.71 (m, 2H), 1.39 (qd, J=12.4,4.4Hz, 2H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (36)
According to the method for step 2 in embodiment 29, by compound (K-8) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (36).
1H NMR(400MHz,DMSO-d
6) δ 10.27 (s, 1H), 8.44 (d, J=2.0Hz, 1H), 7.95 (d, J=2.0Hz, 1H), 7.76 (dt, J=8.6,6.3Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 7.63-7.54 (m, 1H), 7.37 (s, 1H), 7.28-7.17 (m, 2H), 4.08 (d, J=6.4Hz, 2H), 3.95-3.87 (m, 2H), 3.64 (s, 3H), 3.37 (dt, J=11.6,2.0Hz, 2H), 2.90 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.19-2.05 (m, 1H), 1 .85-1.74 (m, 2H), 1.49-1.35 (m, 2H).
MS(ESI+)m/z 586.2[M+H]
+。
Embodiment 37:N- (5- (8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (37)
The bromo- 8- of step 1:6- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup)-N, the preparation of 4- dimethyl quinazoline -2- amine (K-9)
According to the method for step 1 in embodiment 29, by compound (J-19) prepare compound (K-9).
1H NMR(400MHz,DMSO-d
6) δ 7.72 (d, J=2.0Hz, 1H), 7.35 (d, J=2.0Hz, 1H), 7.32 (q, J=4.8Hz, 1H), 5.04-4.92 (m, 1H), 3.78 (dt, J=12.0,4.4Hz, 1H), 3.58 (t, J=10.0Hz, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.01-1.83 (m, 2H), 1.67-1.43 (m, 2H), 1.29 (s, 3H), 1.17 (s, 3H).
Step 2:N- (5- (8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (37) preparation
According to the method for step 2 in embodiment 29, by compound (K-9) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (37).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.79-7.71 (m, 2H), 7.59 (ddd, J=10.4,9.2,2.4Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 7.27 (q, J=4.8Hz, 1H), 7.25-7.18 (m, 1H), 5.16-4.97 (m, 1H), 3.85-3.76 (m, 1H), 3.64 (s, 3H), 3.62-3.53 (m, 1H), 2.90 (d, J=4.8Hz, 3H), 2.76 (s, 3H), 2.04-1.91 (m, 2H) , 1.66-1.50 (m, 2H), 1.29 (s, 3H), 1.18 (s, 3H).
MS(ESI+)m/z 600.2[M+H]
+。
Embodiment 38:N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (38)
The preparation of the bromo- N of step 1:6-, 4- dimethyl -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -2- amine (K-10)
According to the method for step 1 in embodiment 29, by compound (J-21) prepare compound (K-10).
1H NMR(400MHz,DMSO-d
6) δ 7.68 (d, J=2.0Hz, 1H), 7.30 (d, J=4.8Hz, 1H), 7.28 (d, J=1.7Hz, 1H), 4.18-4.07 (m, 1H), 4.07-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.74-3.58 (m, 2H), 2.87 (d, J=4.8Hz, 3H), 2.78-2.68 (m, 1H), 2.66 (s, 3H), 2.10-1.96 (m, 1H), 1.82-1.68 (m, 1H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (38)
According to the method for step 2 in embodiment 29, by compound (K-10) prepare compound (38).
1H NMR(400MHz,DMSO-d
6) δ 10.27 (s, 1H), 8.44 (d, J=2.1Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.75 (dt, J=8.6,6.4Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.63-7.53 (m, 1H), 7.41 (s, 1H), 7.28-7.16 (m, 2H), 4.26-4.16 (m, 1H), 4.11 (dd, J=9.2,8.0Hz, 1H), 3.89-3.79 (m, 2H), 3.70 (dt, J=8.0,6.4Hz, 2H), 3.63 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.82-2.7 0 (m, 4H), 2.12-2.00 (m, 1H), 1.85-1.72 (m, 1H).
MS(ESI+)m/z 572.2[M+H]
+。
Embodiment 39:N- (5- (8- (cyclohexyl oxygroup) -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (39)
The preparation of the bromo- 8- of step 1:6- (cyclohexyl oxygroup)-N, 4- dimethyl quinazoline -2- amine (K-11)
According to the method for step 1 in embodiment 29, by compound (J-22) prepare compound (K-11).
1H NMR(400MHz,DMSO-d
6) δ 7.70 (d, J=2.0Hz, 1H), 7.34-7.25 (m, 2H), 4.69-4.54 (m, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 1.98-1.86 (m, 2H), 1.82-1.71 (m, 2H), 1.61-1.45 (m, 3H), 1.41-1.27 (m, 3H).
The preparation of step 2:N- (5- (8- (cyclohexyl oxygroup) -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (39)
According to the method for step 2 in embodiment 29, by compound (K-11) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (39).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.42 (d, J=2.4Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.70 (d, J=1.2Hz, 1H), 7.59 (ddd, J=10.4,9.2,2.4Hz, 1H), 7.41 (d, J=1.2Hz, 1H), 7.28-7.18 (m, 2H), 4.76-4.66 (m, 1H), 3.65 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.04-1.91 (m, 2H), 1.88-1.73 (m, 2H), 1.67-1. 47 (m, 3H), 1.39-1.27 (m, 3H).
MS(ESI+)m/z 570.2[M+H]
+。
Embodiment 40:N- (5- (8- (cyclopentyloxy) -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (40)
The preparation of step 1:6- bromo- 8- (cyclopentyloxy)-N, 4- dimethyl quinazoline -2- amine (K-12)
According to the method for step 1 in embodiment 29, by compound (J-23) prepare compound (K-12).
1H NMR(400MHz,DMSO-d
6) δ 7.66 (d, J=2.0Hz, 1H), 7.27 (q, J=4.8Hz, 1H), 7.20 (s, 1H), 5.11-4.98 (m, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 1.98-1.85 (m, 2H), 1.84-1.68 (m, 4H), 1.68-1.53 (m, 2H).
The preparation of step 2:N- (5- (8- (cyclopentyloxy) -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (40)
According to the method for step 1 in embodiment 29, by compound (K-12) prepare compound (40).
1H NMR(400MHz,DMSO-d
6) δ 10.28 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.67 (d, J=1.6Hz, 1H), 7.64-7.55 (m, 1H), 7.32 (s, 1H), 7.27-7.17 (m, 2H), 5.20-5.13 (m, 1H), 3.65 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 1.99-1.87 (m, 2H), 1.87-1.75 (m, 4H), 1.69-1.55 (m, 2H).
MS(ESI+)m/z 556.2[M+H]
+。
Embodiment 41:N- (5- (8- cyclobutoxy group -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (41)
The bromo- 8- cyclobutoxy group of step 1:6- -- N, 4- dimethyl quinazoline -2- amine (K-13)
According to the method for step 1 in embodiment 29, by compound (J-24) prepare compound (K-13).
1H NMR(400MHz,DMSO-d
6) δ 7.65 (d, J=2.0Hz, 1H), 7.30 (br s, 1H), 7.01 (d, J=1.6Hz, 1H), 4.84 (p, J=7.2Hz, 1H), 2.88 (d, J=4.8Hz, 3H), 2.65 (s, 3H), 2.49-2.42 (m, 2H), 2.19-2.03 (m, 2H), 1.89-1.75 (m, 1H), 1.74-1.58 (m, 1H).
Step 2:N- (5- (8- cyclobutoxy group -4- methyl -2- (methylamino) quinazoline -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (41)
According to the method for step 2 in embodiment 29, by compound (K-13) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (41).
1H NMR(400MHz,DMSO-d
6) δ 10.29 (s, 1H), 8.41 (d, J=2.4Hz, 1H), 7.91 (d, J=2.4Hz, 1H), 7.77 (dt, J=8.6,6.4Hz, 1H), 7.59 (ddd, J=10.4,9.2,2.4Hz 1H), 7.31-7.17 (m, 2H), 7.14 (d, J=1.2Hz, 1H), 5.05-4.88 (m, 1H), 3.66 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.55-2.45 (m, 2H), 2.22-2.09 (m, 2H), 1.90-1.78 (m, 1H), 1.76-1.61 ( M, 1H).
MS(ESI+)m/z:542.2[M+H]
+。
Embodiment 42:N- (6- (5- ((2,4 difluorobenzene base) sulfoamido) -6- methoxypyridine -3- base) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- base) acetamide (42)
The preparation of step 1:N- (the bromo- 4- methyl -8- of 6- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- base) acetamide (K-14)
Chloroacetic chloride (234mg, 3mmol) is added to compound (J-1) (338mg, 1mmol) and pyridine (396mg, 5mmol) in the mixture in DMF (10mL) at room temperature.4h is stirred at room temperature in the reaction mixture of generation.With water (50mL) diluted reaction mixture, being acidified to pH value with 2M aqueous hydrochloric acid solution is 5, is extracted with ethyl acetate (30mL × 3).The organic layer merged is washed with water (30mL × 2) and saline solution (30mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow solid (290mg, 76%) that residue, which obtains product (K-14) through flash chromatography column (silica gel, methylene chloride/methanol=70:1) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.57 (s, 1H), 7.94 (d, J=2.0Hz, 1H), 7.61 (d, J=2.0Hz, 1H), 5.07-4.94 (m, 1H), 3.93-3.85 (m, 2H), 3.55-3.47 (m, 2H), 2.81 (s, 3H), 2.34 (s, 3H), 2.09-1.93 (m, 2H), 1.74-1.58 (m, 2H).
The preparation of step 2:N- (6- (5- ((2,4 difluorobenzene base) sulfoamido) -6- methoxypyridine -3- base) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- base) acetamide (42)
According to the method for step 4 in embodiment 1, by compound (K-14) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (42).
1H NMR(400MHz,DMSO-d
6) δ 10.55 (s, 1H), 10.32 (s, 1H), 8.52 (d, J=2.0Hz, 1H), 8.06 (d, J=2.0Hz, 1H), 7.91 (d, J=1.0Hz, 1H), 7.76 (dt, J=8.6,6.8Hz, 1H), 7.69 (d, J=1.0Hz, 1H), 7.64-7.55 (m, 1H), 7.22 (dt, J=8.8,2.4Hz, 1H), 5.16-5.07 (m, 1H), 3.96-3.89 (m, 2H), 3.65 (s, 3H), 3.58-3.45 (m, 2H), 2.91 (s, 3H), 2.36 (s, 3H), 2.09-1.9 9 (m, 2H), 1.79-1.63 (m, 2H).
MS(ESI+)m/z:600.2[M+H]
+。
Embodiment 43:N- (6- (6- methoxyl group -5- (methylsulfonyl amido) pyridin-3-yl) -4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -2- base) acetamide (43)
According to the method for step 4 in embodiment 1, by compound (K-14) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (43).
1H NMR(400MHz,DMSO-d
6) δ 10.55 (s, 1H), 9.39 (s, 1H), 8.51 (d, J=2.3Hz, 1H), 8.04 (d, J=2.3Hz, 1H), 7.93 (d, J=1.7Hz, 1H), 7.70 (d, J=1.7Hz, 1H), 5.16-5.08 (m, 1H), 3.99 (s, 3H), 3.97-3.87 (m, 2H), 3.55-3.47 (m, 2H), 3.10 (s, 3H), 2.91 (s, 3H), 2.36 (s, 3H), 2.11-1.98 (m, 2H), 1.78-1.64 (m, 2H).
MS(ESI+)m/z 502.2[M+H]
+。
Embodiment 44:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (44)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline (N-1)
At room temperature to compound (the M) (0.717g that stirred in argon atmosphere, 3mmol), triphenylphosphine (0.944g, 3.6mmol) and tetrahydro -2H- pyrans -4- alcohol (0.368g, DEAD (0.627g, 3.6mmol) 3.6mmol) is added in the solution in anhydrous tetrahydro furan (30mL).The reaction mixture of generation is stirred at room temperature overnight.It is added silica gel (4g), by evaporated under reduced pressure in the mixture of generation.It is yellow solid (0.95g, yield 98%) that residue, which obtains product (N-1) through flash column chromatography (silica gel, DCM/EtOAc=4:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 8.00 (d, J=2.0Hz, 1H), 7.71 (d, J=2.0Hz, 1H), 5.03-4.88 (m, 1H), 3.95-3.87 (m, 2H), 3.58-3.49 (m, 2H), 2.87 (s, 3H), 2.10-2.01 (m, 2H), 1.78-1.61 (m, 2H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (44)
By compound (N-1) (125mg, 0.39mmol), N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide (199mg, it 0.47mmol) deaerates with the mixture of 2M wet chemical (0.585mL, 1.17mmol) in dioxane (7mL), PdCl is then added
2(dppf) (29mg, 0.04mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with ethyl acetate (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is separated, (30mL × 2) water layer is extracted with ethyl acetate.The organic layer merged is washed with water (50mL) and saline solution (50mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow foamy solid (178mg, yield 85%) that residue, which obtains product (44) through flash column chromatography (silica gel, DCM/MeOH=70:1 and then 50:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.08 (s, 1H), 8.56 (d, J=2.3Hz, 1H), 8.11 (d, J=2.3Hz, 1H), 7.94 (d, J=1.6Hz, 1H), 7.81-7.70 (m, 2H), 7.66-7.54 (m, 1H), 7.22 (dt, J=8.8,2.4Hz, 1H), 5.12-4.98 (m, 1H), 3.98-3.90 (m, 2H), 3.66 (s, 3H), 3.61-3.48 (m, 2H), 2.96 (s, 3H), 2.16-2.03 (m, 2H), 1.80-1.65 (m, 2H).
MS(ESI+)m/z 543.1[M+H]
+。
Embodiment 45:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) chloro- 4- fluorobenzenesulfonamide (45) of -2-
According to the method for step 2 in embodiment 44, by compound (N-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) the chloro- 4- fluorobenzenesulfonamide prepare compound (45) of -2-.
1H NMR(400MHz,DMSO-d
6) δ 10.23 (s, 1H), 9.08 (s, 1H), 8.54 (d, J=2.3Hz, 1H), 8.05 (d, J=2.2Hz, 1H), 7.94 (dd, J=8.8,6.0Hz, 1H), 7.90 (d, J=1.6Hz, 1H), 7.77 (dd, J=8.8,2.4Hz, 1H), 7.74 (d, J=1.6Hz, 1H), 7.37 (dt, J=8.4,2.4Hz, 1H), 5.11-5.00 (m, 1H), 3.97-3.90 (m, 2H), 3.67 (s, 3H), 3.58-3.50 (m, 2H), 2.95 (s, 3H), 2.15-2.03 (m, 2 ), H 1.81-1.66 (m, 2H).
MS(ESI+)m/z 559.1[M+H]
+。
Embodiment 46:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide (46)
According to the method for step 2 in embodiment 44, by compound (N-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide prepare compound (46).
1H NMR(400MHz,DMSO-d
6) δ 10.40 (s, 1H), 9.09 (s, 1H), 8.59 (d, J=2.2Hz, 1H), 8.10 (d, J=2.2Hz, 1H), 7.94 (d, J=1.4Hz, 1H), 7.77 (d, J=1.4Hz, 1H), 7.40 (d, J=4.0Hz, 1H), 7.25 (d, J=4.0Hz, 1H), 5.14-5.00 (m, 1H), 3.98-3.90 (m, 2H), 3.76 (s, 3H), 3.62-3.48 (m, 2H), 2.96 (s, 3H), 2.16-2.03 (m, 2H), 1.82-1.66 (m, 2H).
MS(ESI+)m/z 547.1[M+H]
+。
Embodiment 47:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) Methanesulfomide (47)
According to the method for step 2 in embodiment 44, by compound (N-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (47).
1H NMR(400MHz,DMSO-d
6) δ 9.42 (s, 1H), 9.08 (s, 1H), 8.55 (d, J=2.3Hz, 1H), 8.08 (d, J=2.3Hz, 1H), 7.96 (d, J=1.6Hz, 1H), 7.77 (d, J=1.6Hz, 1H), 5.13-4.99 (m, 1H), 4.00 (s, 3H), 3.97-3.90 (m, 2H), 3.61-3.47 (m, 2H), 3.10 (s, 3H), 2.96 (s, 3H), 2.14-2.01 (m, 2H), 1.82-1.66 (m, 2H).
MS(ESI+)m/z 445.2[M+H]
+。
Embodiment 48:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) cyclopropylsulfonamide (48)
According to the method for step 2 in embodiment 44, by compound (N-1) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) cyclopropylsulfonamide prepare compound (48).
1H NMR(400MHz,DMSO-d
6) δ 9.48 (s, 1H), 9.08 (s, 1H), 8.56 (d, J=2.4Hz, 1H), 8.10 (d, J=2.4Hz, 1H), 7.96 (d, J=1.6Hz, 1H), 7.78 (d, J=1.6Hz, 1H), 5.12-5.02 (m, 1H), 4.01 (s, 3H), 3.99-3.90 (m, 2H), 3.60-3.48 (m, 2H), 2.96 (s, 3H), 2.81-2.73 (m, 1H), 2.16-2.03 (m, 2H), 1.81-1.66 (m, 2H), 1.01-0.86 (m, 4H).
MS(ESI+)m/z 471.2[M+H]
+。
Embodiment 49:(R)-N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (49)
Step 1:(R) the bromo- 4- methyl -8- of -6- ((tetrahydrofuran -3- base) oxygroup) quinazoline (N-6) preparation
According to the method for step 1 in embodiment 44, by compound (M) and (S)-tetrahydrofuran -3- alcohol prepare compound (N-6).
1H NMR(400MHz,DMSO-d
6) δ 9.10 (s, 1H), 8.02 (d, J=1.9Hz, 1H), 7.55 (d, J=1.9Hz, 1H), 5.37-5.31 (m, 1H), 4.05-3.85 (m, 3H), 3.83-3.76 (m, 1H), 2.87 (s, 3H), 2.39-2.25 (m, 1H), 2.14-2.01 (m, 1H).
Step 2:(R)-N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (49) preparation
According to the method for step 2 in embodiment 44, by compound (N-6) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (49).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.08 (s, 1H), 8.57 (d, J=2.4Hz, 1H), 8.12 (d, J=2.4Hz, 1H), 7.95 (d, J=1.6Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.65-7.54 (m, 2H), 7.22 (dt, J=8.6,2.4Hz, 1H), 5.51-5,45 (m, 1H), 4.05-3.90 (m, 3H), 3.86-3.78 (m, 1H), 3.66 (s, 3H), 2.96 (s, 3H), 2.40-2.29 (m, 1H), 2.21-2.08 (m, 1H).
MS(ESI+)m/z 529.1[M+H]
+。
Embodiment 50:(R)-N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) Methanesulfomide (50)
According to the method for step 2 in embodiment 44, by compound (N-6) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (50).
1H NMR(400MHz,DMSO-d
6) δ 9.42 (s, 1H), 9.08 (s, 1H), 8.55 (d, J=2.4Hz, 1H), 8.09 (d, J=2.4Hz, 1H), 7.97 (d, J=1.6Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 5.53-5.42 (m, 1H), 4.06-3.90 (m, 6H), 3.86-3.78 (m, 1H), 3.11 (s, 3H), (2.96 s, 3H), 2.41-2.28 (m, 1H), 2.20-2.09 (m, 1H).
MS(ESI+)m/z 431.1[M+H]
+。
Embodiment 51:(S)-N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (51)
Step 1:(S) the bromo- 4- methyl -8- of -6- ((tetrahydrofuran -3- base) oxygroup) quinazoline (N-8) preparation
According to the method for step 1 in embodiment 44, by compound (M) and (R)-tetrahydrofuran -3- alcohol prepare compound (N-8).
1H NMR(400MHz,DMSO-d
6) δ 9.10 (s, 1H), 8.02 (d, J=1.9Hz, 1H), 7.55 (d, J=1.9Hz, 1H), 5.37-5.31 (m, 1H), 4.05-3.85 (m, 3H), 3.83-3.76 (m, 1H), (2.87 s, 3H), 2.39-2.27 (m, 1H), 2.14-2.01 (m, 1H).
Step 2:(S)-N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (51) preparation
According to the method for step 2 in embodiment 44, by compound (N-8) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (51).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.08 (s, 1H), 8.57 (d, J=2.2Hz, 1H), 8.12 (d, J=2.2Hz, 1H), 7.95 (d, J=1.2Hz, 1H), 7.77 (dt, J=8.8,6.6Hz, 1H), 7.66-7.55 (m, 2H), 7.22 (dt, J=8.8,2.4Hz, 1H), 5.52-5.43 (m, 1H), 4.06-3.89 (m, 3H), 3.86-3.78 (m, 1H), 3.66 (s, 3H), 2.96 (s, 3H), 2.40-2.29 (m, 1H), 2.20-2.08 (m, 1H).
MS(ESI+)m/z 529.1[M+H]
+。
Embodiment 52:(S)-N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) oxygroup) quinazoline -6- base) pyridin-3-yl) Methanesulfomide (52)
According to the method for step 2 in embodiment 44, by compound (N-8) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (53).
1H NMR(400MHz,DMSO-d
6) δ 9.42 (s, 1H), 9.08 (s, 1H), 8.55 (d, J=2.3Hz, 1H), 8.09 (d, J=2.3Hz, 1H), 7.98 (d, J=1.6Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 5.51-5.45 (m, 1H), 4.04-3.9 (m, 6H), 3.88-3.76 (m, 1H), 3.11 (s, 3H), 2.96 (s, 3H), 2.42-2.26 (m, 1H), 2.22-2.06 (m, 1H).
MS(ESI+)m/z 431.1[M+H]
+。
Embodiment 53:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (53)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline (N-10)
According to the method for step 1 in embodiment 44, by compound (M) and (tetrahydro -2H- pyrans -4- base) methanol prepare compound (N-10).
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 7.99 (d, J=1.9Hz, 1H), 7.56 (d, J=1.9Hz, 1H), 4.08 (d, J=6.5Hz, 2H), 3.94-3.87 (m, 2H), 3.38 (dt, J=11.8,2.0Hz, 2H), 2.87 (s, 3H), 2.21-2.08 (m, 1H), 1.80-1.72 (m, 2H), 1.48-1.34 (m, 2H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (53)
According to the method for step 2 in embodiment 44, by compound (N-10) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (53).
1H NMR(400MHz,DMSO-d
6) δ 10.34 (s, 1H), 9.08 (s, 1H), (8.58 d, J=2.3Hz, 1H), 8.12 (d, J=2.3Hz, 1H), 7.92 (d, J=1.6Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.62-7.55 (m, 1H), 7.22 (dt, J=8.4,2.2Hz, 1H), 4.17 (d, J=6.5Hz, 2H), 3.96-3.87 (m, 2H), 3.66 (s, 3H), 3.40 (dt, J=11.4,1.8Hz, 2H), 2.96 (s, 3H), 2.26-2.11 (m, 1H), 1.84-1.76 (m, 2H), 1.51-1.38 (m, 2H).
MS(ESI+)m/z 557.2[M+H]
+。
Embodiment 54:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) Methanesulfomide (54)
According to the method for step 2 in embodiment 44, by compound (N-10) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) Methanesulfomide prepare compound (54).
1H NMR(400MHz,DMSO-d
6) δ 9.41 (s, 1H), 9.08 (s, 1H), 8.56 (d, J=2.4Hz, 1H), 8.09 (d, J=2.4Hz, 1H), 7.94 (d, J=1.6Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 4.17 (d, J=6.5Hz, 2H), 4.01 (s, 3H), 3.96-3.88 (m, 2H), 3.39 (dt, J=11.7,1.9Hz, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.25-2.11 (m, 1H), 1.84-1.75 (m, 2H), 1.51-1.37 (m, 2H).
MS(ESI+)m/z 459.2[M+H]
+。
Embodiment 55:N- (5- (8- (cyclohexyl oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (55)
The preparation of the bromo- 8- of step 1:6- (cyclohexyl oxygroup) -4- methylquinazolin (N-12)
According to the method for step 1 in embodiment 44, by compound (M) and cyclohexanol prepare compound (N-12).
1H NMR(400MHz,DMSO-d
6) δ 9.09 (s, 1H), 7.97 (d, J=1.9Hz, 1H), 7.61 (d, J=1.9Hz, 1H), 4.78-4.65 (m, 1H), 2.86 (s, 3H), 2.05-1.93 (m, 2H), 1.82-1.72 (m, 2H), 1.62-1.49 (m, 3H), 1.49-1.37 (m, 2H), 1.37-1.25 (m, 1H).
The preparation of step 2:N- (5- (8- (cyclohexyl oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (55)
According to the method for step 2 in embodiment 44, by compound (N-12) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (55).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.07 (s, 1H), 8.55 (d, J=2.4Hz, 1H), 8.09 (d, J=2.4Hz, 1H), 7.90 (d, J=1.6Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), (7.67 d, J=1.6Hz, 1H), 7.64-7.56 (m, 1H), 7.26-7.19 (m, 1H), 4.90-4.77 (m, 1H), 3.67 (s, 3H), 2.95 (s, 3H), 2.08-1.95 (m, 2H), 1.87-1.73 (m, 2H), 1.65-1.53 (m, 3H), 1.52-1.27 (m, 3 H).
MS(ESI+)m/z 541.2[M+H]
+。
Embodiment 56:N- (5- (8- (cyclopentyloxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (56)
The preparation of step 1:6- bromo- 8- (cyclopentyloxy) -4- methylquinazolin (N-13)
According to the method for step 1 in embodiment 44, by compound (M) and cyclopentanol prepare compound (N-13).
1H NMR(400MHz,DMSO-d
6) δ 9.09 (s, 1H), 7.96 (d, J=2.0Hz, 1H), 7.50 (d, J=2.0Hz, 1H), 5.17-5.06 (m, 1H), 2.86 (s, 3H), 2.09-1.96 (m, 2H), 1.88-1.72 (m, 4H), 1.68-1.57 (m, 2H).
The preparation of step 2:N- (5- (8- (cyclopentyloxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (56)
According to the method for step 2 in embodiment 44, by compound (N-13) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (56).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.06 (s, 1H), 8.55 (d, J=2.4Hz, 1H), 8.08 (d, J=2.4Hz, 1H), 7.90 (d, J=1.6Hz, 1H), 7.77 (dt, J=8.6,6.4Hz, 1H), 7.64-7.57 (m, 1H), 7.57 (d, J=1.6Hz, 1H), 7.27-7.19 (m, 1H), 5.29-5.21 (m, 1H), 3.67 (s, 3H), 2.95 (s, 3H), 2.12-1.96 (m, 2H), 1.94-1.73 (m, 4H), 1.73-1.57 (m, 2H).
MS(ESI+)m/z 527.2[M+H]
+。
Embodiment 57:N- (5- (8- ((4,4- difiuorocyclohexyl) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (57)
The preparation of the bromo- 8- of step 1:6- ((4,4- difiuorocyclohexyl) oxygroup) -4- methylquinazolin (N-14)
According to the method for step 1 in embodiment 44, by compound (M) and 4,4- difluorocyclohex alcohol prepare compound (N-14).
1H NMR(400MHz,DMSO-d
6) δ 9.12 (s, 1H), 8.03 (d, J=1.9Hz, 1H), 7.75 (d, J=1.9Hz, 1H), 5.02-4.94 (m, 1H), 2.87 (s, 3H), 2.25-1.85 (m, 8H).
The preparation of step 2:N- (5- (8- ((4,4- difiuorocyclohexyl) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (57)
According to the method for step 2 in embodiment 44, by compound (N-14) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (57).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.10 (s, 1H), 8.57 (d, J=2.4Hz, 1H), 8.12 (d, J=2.4Hz, 1H), 7.97 (d, J=1.6Hz, 1H), 7.82 (d, J=1.6Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.64-7.55 (m, 1H), 7.22 (dt, J=8.4,2.2Hz, 1H), 5.15-5.05 (m, 1H), 3.66 (s, 3H), 2.96 (s, 3H), 2.31-2.11 (m, 2H), 2.10-1.93 (m, 6H).
MS(ESI+)m/z 577.2[M+H]
+。
Embodiment 58:N- (5- (8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (58)
The preparation of the bromo- 8- of step 1:6- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin (N-15)
According to the method for step 1 in embodiment 44, by compound (M) and 2,2- dimethyl tetrahydro -2H- pyrans -4- alcohol prepare compound (N-15).
1H NMR(400MHz,DMSO-d
6) δ 9.09 (s, 1H), 7.99 (d, J=1.8Hz, 1H), 7.72 (d, J=1.8Hz, 1H), 5.12-4.97 (m, 1H), 3.84-3.62 (m, 2H), 2.86 (s, 3H), 2.14-1.94 (m, 2H), 1.64-1.45 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H).
Step 2:N- (5- (8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- base) oxygroup) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (58) preparation
According to the method for step 2 in embodiment 44, by compound (N-15) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (58).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.07 (s, 1H), 8.57 (d, J=2.4Hz, 1H), 8.12 (d, J=2.4Hz, 1H), 7.93 (d, J=1.6Hz, 1H), 7.81-7.71 (m, 2H), 7.64-7.56 (m, 1H), 7.26-7.19 (m, 1H), 5.24-5.09 (m, 1H), 3.86-3.77 (m, 1H), 3.75-3.67 (m, 1H), 3.66 (s, 3H), 2.96 (s, 3H), 2.14-2.01 (m, 2H), 1.65-1.52 (m, 2H), 1.26 (s, 3H), 1.25 (s, 3H).
MS(ESI+)m/z 571.2[M+H]
+。
Embodiment 59:N- (2- methoxyl group -5- (4- methyl -8- ((3- methy oxetane -3- base) methoxyl group)-quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (59)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((3- methy oxetane -3- base) methoxyl group) quinazoline (N-16)
According to the method for step 1 in embodiment 44, by compound (M) and (3- methy oxetane -3- base) methanol prepare compound (N-16).
1H NMR(400MHz,DMSO-d
6) δ 9.13 (s, 1H), 8.02 (d, J=1.9Hz, 1H), 7.64 (d, J=1.9Hz, 1H), 4.57 (d, J=5.8Hz, 2H), 4.37 (d, J=5.8Hz, 2H), 4.32 (s, 2H), 2.88 (s, 3H), 1.45 (s, 3H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((3- methy oxetane -3- base) methoxyl group)-quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (59)
According to the method for step 2 in embodiment 44, by compound (N-16) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (59).
1H NMR(400MHz,DMSO-d
6) δ 10.34 (s, 1H), 9.10 (s, 1H), 8.59 (d, J=2.4Hz, 1H), 8.14 (d, J=2.4Hz, 1H), 7.96 (d, J=1.6Hz, 1H), 7.80-7.74 (m, 1H), 7.73 (d, J=1.6Hz, 1H), 7.64-7.56 (m, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 4.61 (d, J=5.8Hz, 2H), 4.41 (s, 2H), 4.40 (d, J=5.8Hz, 2H), 3.65 (s, 3H), 2.97 (s, 3H), 1.49 (s, 3H).
MS(ESI+)m/z 543.1[M+H]
+。
Embodiment 60:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -2- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (60)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((tetrahydrofuran -2- base) methoxyl group) quinazoline (N-17)
According to the method for step 1 in embodiment 44, by compound (M) and tetrahydrofurfuryl alcohol prepare compound (N-17).
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 7.99 (d, J=1.8Hz, 1H), 7.57 (d, J=1.8Hz, 1H), 4.34-4.25 (m, 1H), 4.24-4.12 (m, 2H), 3.83 (dd, J=14.2,7.2Hz, 1H), 3.71 (dd, J=14.2,7.2Hz, 1H), 2.87 (s, 3H), 2.11-1.92 (m, 2H), 1.90-1.70 (m, 2H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -2- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (60)
According to the method for step 2 in embodiment 44, by compound (N-17) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (60).
1H NMR(400MHz,DMSO-d
6) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.58 (d, J=2.2Hz, 1H), 8.13 (d, J=2.2Hz, 1H), 7.93 (d, J=1.2Hz, 1H), 7.76 (dt, J=8.4,6.4Hz, 1H), 7.65 (d, J=1.2Hz, 1H), 7.64-7.55 (m, 1H), 7.21 (dt, J=8.6,2.2Hz, 1H), 4.39-4.21 (m, 3H), 3.86 (dd, J=14.2,7.0Hz, 1H), 3.73 (dd, J=14.2,7.0Hz, 1H), 3.65 (s, 3H), 2.96 (s, 3H), 2.1 4-1.93 (m, 2H), 1.93-1.73 (m, 2H).
MS(ESI+)m/z 543.1[M+H]
+。
Embodiment 61:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (61)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((tetrahydrofuran -3- base) methoxyl group) quinazoline (N-18)
According to the method for step 1 in embodiment 44, by compound (M) and (tetrahydrofuran -3- base) methanol prepare compound (N-18).
1H NMR(400MHz,DMSO-d
6) δ 9.12 (s, 1H), 8.00 (d, J=1.8Hz, 1H), 7.59 (d, J=1.8Hz, 1H), 4.21-4.08 (m, 2H), 3.91-3.75 (m, 2H), 3.74-3.59 (m, 2H), 2.87 (s, 3H), 2.84-2.75 (m, 1H), 2.11-2.02 (m, 1H), 1.80-1.69 (m, 1H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((tetrahydrofuran -3- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (61)
According to the method for step 2 in embodiment 44, by compound (N-18) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (61).
1H NMR(400MHz,DMSO-d
6) δ 10.34 (s, 1H), 9.09 (s, 1H), 8.58 (d, J=2.2Hz, 1H), 8.13 (d, J=2.2Hz, 1H), 7.94 (d, J=1.0Hz, 1H), 7.76 (dd, J=8.6,6.6Hz, 1H), 7.67 (d, J=1.0Hz, 1H), 7.65-7.53 (m, 1H), 7.22 (dt, J=8.6,2.4Hz, 1H), 4.35-4.16 (m, 2H), 3.93-3.78 (m, 2H), 3.75-3.60 (m, 5H), 2.96 (s, 3H), 2.92-2.76 (m, 1H), 2.16-2.05 (m, 1H) 1.83-1.73 (m, 1H).
MS(ESI+)m/z 543.1[M+H]
+。
Embodiment 62:N- (2- methoxyl group -5- (4- methyl -8- ((1- methyl piperidine -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (62)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((1- methyl piperidine -4- base) oxygroup) quinazoline (N-19)
According to the method for step 1 in embodiment 44, by compound (M) and 1- methyl piperidine -4- alcohol prepare compound (N-19).
1H NMR(400MHz,DMSO-d
6) δ 9.10 (s, 1H), 7.99 (d, J=1.9Hz, 1H), 7.64 (d, J=1.9Hz, 1H), 4.80-4.66 (m, 1H), 2.88-2.85 (m, 3H), 2.74-2.63 (m, 2H), 2.30-2.14 (m, 6H), 2.07-1.95 (m, 2H), 1.82-1.69 (m, 2H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((1- methyl piperidine -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (62)
According to the method for step 2 in embodiment 44, by compound (N-19) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (62).
1H NMR(400MHz,DMSO-d
6) δ 9.07 (s, 1H), 8.35 (d, J=2.2Hz, 1H), 7.93 (d, J=2.2Hz, 1H), (7.86 d, J=1.6Hz, 1H), 7.79 (dt, J=8.6,6.6Hz, 1H), (7.66 d, J=1.6Hz, 1H), 7.54-7.44 (m, 1H), 7.18 (dt, J=8.4,2.4Hz, 1H), 4.95-4.82 (m, 1H), 3.70 (s, 3H), 2.94 (s, 3H), 2.93-2.86 (m, 2H), 2.51 (s, 1H), 2.39 (s, 3H), 2.15-2.04 (m, 2H), 1.92-1.80 (m , 2H).
MS(ESI+)m/z 556.2[M+H]
+。
Embodiment 63:N- (2- methoxyl group -5- (4- methyl -8- (2- (pyrrolidin-1-yl) ethyoxyl) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (63)
The preparation of the bromo- 4- methyl -8- of step 1:6- (2- (pyrrolidin-1-yl) ethyoxyl) quinazoline (N-20)
According to the method for step 1 in embodiment 44, by compound (M) and 2- (pyrrolidin-1-yl) second -1- alcohol prepare compound (N-20).
1H NMR(400MHz,DMSO-d
6) δ 9.10 (s, 1H), 7.99 (d, J=1.9Hz, 1H), 7.58 (d, J=1.9Hz, 1H), 4.30 (t, J=5.8Hz, 2H), 2.93 (t, J=5.8Hz, 2H), (2.87 s, 3H), 2.64-2.55 (m, 4H), 1.76-1.62 (m, 4H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- (2- (pyrrolidin-1-yl) ethyoxyl) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (63)
According to the method for step 2 in embodiment 44, by compound (N-20) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (63).
1H NMR(400MHz,DMSO-d
6) δ 9.08 (s, 1H), 8.37 (d, J=2.2Hz, 1H), 7.96 (d, J=2.2Hz, 1H), 7.86 (d, J=1.4Hz, 1H), 7.80 (dt, J=8.6,6.6Hz, 1H), 7.61 (d, J=1.4Hz, 1H), 7.53-7.45 (m, 1H), (7.19 dt, J=8.4,2.4Hz, 1H), 4.45 (t, J=5.5Hz, 2H), 3.69 (s, 3H), 3.18 (t, J=5.5Hz, 2H), 2.95 (s, 3H), 2.91-2.81 (m, 4H), 1.83-1.75 (m, 4H).
MS(ESI+)m/z 556.2[M+H]
+。
Embodiment 64:N- (5- (8- (2- (1H- pyrazol-1-yl) ethyoxyl) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (64)
The preparation of step 1:8- (2- (1H- pyrazol-1-yl) ethyoxyl) bromo- 4- methylquinazolin (N-21) of -6-
According to the method for step 1 in embodiment 44, by compound (M) and 2- (1H- pyrazol-1-yl) second -1- alcohol prepare compound (N-21).
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 8.01 (d, J=1.9Hz, 1H), 7.87 (dd, J=2.2,0.6Hz, 1H), 7.54 (d, J=1.9Hz, 1H), 7.46 (dd, J=1.8,0.6Hz, 1H), 6.24 (t, J=2.0Hz, 1H), 4.65-4.57 (m, 4H), 2.86 (s, 3H).
The preparation of step 2:N- (5- (8- (2- (1H- pyrazol-1-yl) ethyoxyl) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (64)
According to the method for step 2 in embodiment 44, by compound (N-21) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (64).
1H NMR(400MHz,DMSO-d
6) δ 10.33 (s, 1H), 9.09 (s, 1H), 8.56 (d, J=2.3Hz, 1H), 8.12 (d, J=2.3Hz, 1H), 7.95 (d, J=1.6Hz, 1H), 7.92 (dd, J=2.2,0.6Hz, 1H), 7.76 (dt, J=8.4,6.4Hz, 1H), 7.62 (d, J=1.6Hz, 1H), 7.61-7.56 (m, 1H), 7.46 (dd, J=1.8,0.6Hz, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 6.27-6.23 (m, 1H), 4.76-4.60 (m, 4H), 3.65 (s, 3H) 2.95 (s, 3H).
MS(ESI+)m/z 553.1[M+H]
+。
Embodiment 65:N- (2- methoxyl group -5- (4- methyl -8- (2- morpholine base oxethyl) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (65)
The preparation of step 1:4- (2- ((the bromo- 4- methylquinazolin -8- base of 6-) oxygroup) ethyl) morpholine (N-22)
According to the method for step 1 in embodiment 44, by compound (M) and 2- morpholinyl second -1- alcohol prepare compound (N-22).
1H NMR(400MHz,DMSO-d
6) δ 9.10 (s, 1H), 7.99 (d, J=1.9Hz, 1H), 7.61 (d, J=1.9Hz, 1H), 4.33 (t, J=5.7Hz, 2H), 3.63-3.53 (m, 4H), 2.87 (s, 3H), 2.82 (t, J=5.7Hz, 2H), 2.59-2.51 (m, 4H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- (2- morpholine base oxethyl) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (65)
According to the method for step 2 in embodiment 44, by compound (N-22) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (65).
1H NMR(400MHz,DMSO-d
6) δ 10.33 (s, 1H), 9.08 (s, 1H), 8.57 (d, J=2.4Hz, 1H), 8.12 (d, J=2.4Hz, 1H), 7.93 (d, J=1.6Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.67 (d, J=1.6Hz, 1H), 7.59 (ddd, J=10.6,9.2,2.4Hz, 1H), 7.27-7.18 (m, 1H), 4.43 (t, J=5.6Hz, 2H), 3.66 (s, 3H), 3.64-3.57 (m, 4H), 2.96 (s, 3H), 2.89 (t, J=5.6Hz, 2H), 2.65-2.56 (m, 4H).
MS(ESI+)m/z 571.2[M+H]
+。
Embodiment 66:N- (2- methoxyl group -5- (4- methyl -8- ((1- methyl piperidine -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (66)
The preparation of the bromo- 4- methyl -8- of step 1:6- ((1- methyl piperidine -4- base) methoxyl group) quinazoline (N-23)
According to the method for step 1 in embodiment 44, by compound (M) and (1- methyl piperidine -4- base) methanol prepare compound (N-23).
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 7.98 (d, J=1.8Hz, 1H), 7.54 (d, J=1.8Hz, 1H), 4.06 (d, J=6.0Hz, 2H), 2.86 (s, 3H), 2.84-2.76 (m, 1H), 2.17 (s, 3H), 1.95-1.75 (m, 5H), 1.44-1.31 (m, 2H).
The preparation of step 2:N- (2- methoxyl group -5- (4- methyl -8- ((1- methyl piperidine -4- base) methoxyl group) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (66)
According to the method for step 2 in embodiment 44, by compound (N-23) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (66).
1H NMR(400MHz,DMSO-d
6) δ 9.06 (s, 1H), 8.25 (d, J=1.6Hz, 1H), 7.86-7.80 (m, 2H), 7.78 (d, J=1.4Hz, 1H), 7.51 (d, J=1.4Hz, 1H), 7.43 (dt, J=9.8,2.4Hz, 1H), 7.16 (dt, J=8.4,2.4Hz, 1H), 4.15 (d, J=6.0Hz, 2H), 3.72 (s, 3H), 3.16-3.07 (m, 2H), 2.93 (s, 3H), 2.48-2.34 (m, 5H), 2.08-1.87 (m, 3H), 1.61-1.41 (m, 2H).
MS(ESI+)m/z 570.2[M+H]
+。
Embodiment 67:N- (5- (8- (2- (dimethylamino) ethyoxyl) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (67)
Step 1:2- ((the bromo- 4- methylquinazolin -8- base of 6-) methoxyl group)-N, the preparation of N- dimethyl ethanol -1- amine (N-24)
According to the method for step 1 in embodiment 44, by compound (M) and 2- (dimethylamino) second -1- alcohol prepare compound (N-24).
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 8.03 (d, J=1.9Hz, 1H), 7.63 (d, J=1.9Hz, 1H), 4.40 (t, J=5.2Hz, 2H), 3.03 (t, J=5.2Hz, 2H), 2.88 (s, 3H), 2.48 (s, 6H).
The preparation of step 2:N- (5- (8- (2- (dimethylamino) ethyoxyl) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (67)
According to the method for step 2 in embodiment 44, by compound (N-24) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (67).
1H NMR(400MHz,DMSO-d
6) δ 9.08 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 8.01 (d, J=2.3Hz, 1H), 7.89 (d, J=1.6Hz, 1H), 7.79 (dt, J=8.6,6.4Hz, 1H), 7.64 (d, J=1.6Hz, 1H), 7.56-7.48 (m, 1H), 7.24-7.16 (m, 1H), (4.43 t, J=5.6Hz, 2H), 3.68 (s, 3H), 2.98 (t, J=5.6Hz, 2H), 2.95 (s, 3H), 2.44 (s, 6H).
MS(ESI+)m/z 530.2[M+H]
+。
Embodiment 68:N- (5- (8- (cyclo propyl methoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (68)
The preparation of step 1:6- bromo- 8- (cyclo propyl methoxy) -4- methylquinazolin (N-25)
To compound (the M) (0.120g that stirred in seal pipe, 0.5mmol), the mixture of cyclopropyl methyl bromide (0.675g, 5mmol) and potassium carbonate (0.691g, 5mmol) in acetonitrile (8mL) is stirred overnight at 85 DEG C.The mixture of generation is cooled to room temperature, is then filtered.Silica gel (1g) is added into filtrate, by the mixture evaporated under reduced pressure of generation.It is yellow oil (0.142g, yield 97%) that residue, which obtains product (N-25) through flash column chromatography (silica gel, DCM/MeOH=150:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 9.11 (s, 1H), 7.97 (d, J=2.0Hz, 1H), 7.49 (d, J=2.0Hz, 1H), 4.05 (d, J=7.1Hz, 2H), 2.87 (s, 3H), 1.41-1.29 (m, 1H), 0.68-0.57 (m, 2H), 0.43-0.36 (m, 2H).
The preparation of step 2:N- (5- (8- (cyclo propyl methoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (68)
According to the method for step 2 in embodiment 44, by compound (N-25) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (68).
1H NMR(400MHz,DMSO-d
6) δ 10.33 (s, 1H), 9.08 (s, 1H), 8.55 (d, J=2.2Hz, 1H), 8.09 (d, J=2.2Hz, 1H), 7.91 (d, J=1.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.63-7.57 (m, 1H), 7.57 (d, J=1.4Hz, 1H), 7.21 (dt, J=8.4,2.4Hz, 1H), 4.15 (d, J=7.0Hz, 2H), 3.65 (s, 3H), 2.96 (s, 3H), 1.47-1.32 (m, 1H), 0.71-0.60 (m, 2H), 0.46-0.37 (m, 2H).
MS(ESI+)m/z 513.1[M+H]
+。
Embodiment 69:N- (5- (8- isopropoxy base -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (69)
The preparation of the bromo- 8- isopropoxy -4- methylquinazolin (N-26) of step 1:6-
According to the method for step 1 in embodiment 68, by compound (M) and isopropyl bromide prepare compound (N-26).
1H NMR(400MHz,DMSO-d
6) δ 9.08 (s, 1H), 7.97 (d, J=2.0Hz, 1H), 7.57 (d, J=2.0Hz, 1H), 5.00-4.89 (m, 1H), 2.86 (s, 3H), 1.37 (d, J=6.0Hz, 6H).
The preparation of step 2:N- (5- (8- isopropoxy -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (69)
According to the method for step 2 in embodiment 44, by compound (H-26) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepares title compound (69).
1H NMR(400MHz,DMSO-d
6) δ 10.34 (s, 1H), 9.06 (s, 1H), 8.55 (d, J=2.3Hz, 1H), 8.08 (d, J=2.3Hz, 1H), 7.91 (d, J=1.6Hz, 1H), 7.77 (dt, J=8.6,6.4Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.62-7.55 (m, 1H), 7.22 (dt, J=8.4,2.2Hz, 1H), 5.13-5.02 (m, 1H), 3.67 (s, 3H), 2.95 (s, 3H), (1.40 d, J=6.0Hz, 6H).
MS(ESI+)m/z 501.1[M+H]
+。
Embodiment 70:N- (5- (8- cyclobutoxy group -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (70)
The preparation of the bromo- 8- cyclobutoxy group -4- methylquinazolin (N-27) of step 1:6-
According to the method for step 1 in embodiment 68, by compound (M) and cyclobutyl bromine prepare compound (N-27).
1H NMR(400MHz,DMSO-d
6) δ 9.10 (s, 1H), 7.99 (d, J=1.9Hz, 1H), 7.33 (d, J=1.9Hz, 1H), 4.97 (p, J=7.2Hz, 1H), 2.86 (s, 3H), 2.59-2.52 (m, 2H), 2.23-2.08 (m, 2H), 1.91-1.80 (m, 1H), 1.79-1.61 (m, 1H).
The preparation of step 2:N- (5- (8- cyclobutoxy group -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (70)
According to the method for step 2 in embodiment 44, by compound (N-27) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (70).
1H NMR(400MHz,DMSO-d
6) δ 10.36 (s, 1H), 9.07 (s, 1H), 8.54 (d, J=2.2Hz, 1H), 8.07 (d, J=2.2Hz, 1H), 7.92 (s, 1H), 7.76 (dt, J=8.4,6.4Hz, 1H), 7.64-7.56 (m, 1H), 7.40 (s, 1H), 7.23 (dt, J=8.4,2.4Hz, 1H), 5.16-5.02 (m, 1H), 3.68 (s, 3H), 2.95 (s, 3H), 2.62-2.52 (m, 2H), 2.29-2.10 (m, 2H), 1.94-1.81 (m, 1H), 1.80-1.65 (m, 1H).
MS(ESI+)m/z 513.1[M+H]
+。
Embodiment 71:N- (5- (8- (difluoro-methoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (71)
The preparation of step 1:6- bromo- 8- (difluoro-methoxy) -4- methylquinazolin (N-28)
To compound (the M) (0.120g that stirred in seal pipe, 0.5mmol), chlorine methyl difluoroacetate (0.217g, 1.5mmol) and the mixture of sodium carbonate (0.159g, 1.5mmol) in dimethylformamide (3mL) stirs 8h at 70 DEG C.The mixture of generation is cooled to room temperature, is diluted with water (30mL), (30mL × 3) is extracted with ethyl acetate.The organic layer merged is washed with water (30mL) and saline solution (30mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow oil (0.080g, yield 55%) that residue, which is prepared thin-layer chromatography (silica gel, DCM/MeOH=40:1, v/v) purifying and obtains product (N-28),.
1H NMR(400MHz,DMSO-d
6) δ 9.21 (s, 1H), 8.43 (d, J=2.0Hz, 1H), 7.98 (d, J=2.0Hz, 1H), 7.53 (t, J=73.8Hz, 1H), 2.94 (s, 3H).
The preparation of step 2:N- (5- (8- (difluoro-methoxy) -4- methylquinazolin -6- base) -2- methoxypyridine -3- base) -2,4 difluorobenzene sulfonamide (71)
According to the method for step 2 in embodiment 44, by compound (N-28) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (71).
1H NMR(400MHz,DMSO-d
6) δ 10.37 (s, 1H), 9.18 (s, 1H), (8.59 d, J=2.4Hz, 1H), 8.35 (d, J=1.8Hz, 1H), 8.16 (d, J=2.4Hz, 1H), 8.06 (d, J=1.8Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.64-7.55 (m, 1H), 7.56 (t, J=74.0Hz, 1H), 7.21 (dt, J=8.4,2.0Hz, 1H), 3.66 (s, 3H), 3.03 (s, 3H).
Embodiment 72:N- (2- methoxyl group -5- (8- methoxyl group -4- methylquinazolin -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (72)
According to the method for step 2 in embodiment 44, by compound (L) and N- (2- methoxyl group -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyridin-3-yl) -2,4- difluorobenzenesulfonamide prepare compound (72).
1H NMR(400MHz,DMSO-d
6) δ 10.35 (s, 1H), 9.06 (s, 1H), 8.58 (d, J=2.2Hz, 1H), 8.13 (d, J=2.2Hz, 1H), 7.93 (d, J=1.6Hz, 1H), 7.77 (dt, J=8.4,6.4Hz 1H), 7.65-7.54 (m, 2H), 7.23 (dt, J=8.6,2.4Hz, 1H), 4.08 (s, 3H), 3.67 (s, 3H), 2.96 (s, 3H).
MS(ESI+)m/z 473.1[M+H]
+。
Embodiment 73:N- (the chloro- 5- of 2- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -4- fluorobenzenesulfonamide (73)
By compound (N-1) (71mg, 0.22mmol), acetic anhydride potassium (65mg, 0.66mmol) and connection pinacol borate (64mg, 0.25mmol) the mixture degassing in dioxane (8mL), is then added PdCl
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, stir 4h in argon atmosphere at 100 DEG C.After being cooled to room temperature, N- (the bromo- 2- chloropyridine -3- base of 5-) -4- fluorobenzenesulfonamide (91mg, 0.25mmol) and 2M wet chemical (0.44mL, 0.88mmol) are added into the mixture of generation.The mixture of generation is deaerated, PdCl is then added
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with ethyl acetate (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is separated, (30mL × 2) water layer is extracted with ethyl acetate.The organic layer merged is washed with water (50mL) and saline solution (50mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow foamy solid (42mg, yield 35%) that residue, which obtains product (73) through thin layer preparation chromatography (DCM/MeOH=15:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.57 (s, 1H), 9.12 (s, 1H), 8.79 (d, J=2.2Hz, 1H), 8.16 (d, J=2.2Hz, 1H), 8.00 (d, J=1.6Hz, 1H), 7.87-7.80 (m, 2H), 7.78 (d, J=1.6Hz, 1H), 7.50-7.39 (m, 2H), 5.12-5.00 (m, 1H), 3.98-3.90 (m, 2H), 3.60-3.50 (m, 2H), 2.97 (s, 3H), 2.15-2.02 (m, 2H), 1.82-1.65 (m, 2H).
MS(ESI+)m/z 529.1[M+H]
+。
Embodiment 74:N- (2- methyl -5- (4- methyl -8- ((tetrahydro -2H- pyrans -4- base) oxygroup) quinazoline -6- base) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (74)
By compound (N-1) (71mg, 0.22mmol), acetic anhydride potassium (65mg, 0.66mmol) and connection pinacol borate (64mg, 0.25mmol) the mixture degassing in dioxane (8mL), is then added PdCl
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, stir 4h in argon atmosphere at 100 DEG C.After being cooled to room temperature, N- (5- bromine-2-methylpyridine -3- base) -2,4- difluorobenzenesulfonamide (91mg, 0.25mmol) and 2M wet chemical (0.44mL, 0.88mmol) are added into the mixture of generation.The mixture of generation is deaerated, PdCl is then added
2(dppf) (16mg, 0.022mmol).Reaction mixture degassing and backfilled with argon (three circulations) by generation, then stir 5h in argon atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature, is diluted with ethyl acetate (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is separated, (30mL × 2) water layer is extracted with ethyl acetate.The organic layer merged is washed with water (50mL) and saline solution (50mL), is dried, filtered with anhydrous sodium sulfate, is concentrated.It is yellow foamy solid (46mg, yield 40%) that residue, which obtains product (74) through thin layer preparation chromatography (DCM/MeOH=15:1, v/v) purifying,.
1H NMR(400MHz,DMSO-d
6) δ 10.53 (s, 1H), 9.10 (s, 1H), 8.84 (s, 1H), 7.88 (d, J=1.6Hz, 1H), 7.85 (d, J=2.0Hz, 1H), 7.80 (dt, J=8.6,6.4Hz, 1H), (7.71 d, J=1.6Hz, 1H), 7.67-7.59 (m, 1H), 7.30-7.24 (m, 1H), 5.08-4.99 (m, 1H), 3.97-3.90 (m, 2H), 3.58-3.50 (m, 2H), 2.94 (s, 3H), 2.34 (s, 3H), 2.16-2.01 (m, 2H), 1.82-1.64 (m, 2H).
MS(ESI+)m/z 527.2[M+H]
+。
Pharmacological activity evaluation
Experimental example 1: biochemistry detects PI3K alpha active
Using vitro kinase check and evaluation the compound of the present invention to the efficiency of PI3K α.Using the luminescence detection based on luciferase, the kinase activity of PI3K- α is measured by generated ADP level in detection kinase reaction.Kinase-Glo
TMKinase assay kit is purchased from Promega company.All detections carry out at room temperature, use OptiPlate
TM- 384 white 384 orifice plates.PI3K alpha kinase comes from Invitrogen.Substrate is PIP2 (Invitrogen).Kinase buffer liquid includes 50mM Hepes (pH 7.5), 3mM MgCl
2, 100mM NaCl, 1mM EGTA, 0.03%CHAPS and 2mM DTT.PI3K alpha kinase solution is prepared by the way that PI3K alpha kinase is diluted to 6.6nM in kinase buffer liquid.Substrate solution includes 100 μM of PIP2 and 50 μM of ATP.Untested compound is diluted to 10mM in 100%DMSO, 3 times of serial dilutions are then pressed in 100%DMSO into 10 various concentrations.Then the compound being diluted in 100%DMSO is diluted 25 times in 1 × kinase buffer liquid.The PI3K alpha kinase solution of the diluted compound solution of 2.5 μ L and 2.5 μ L is added in each hole of 384 orifice plates.Substrate solution by the way that every 5 μ L of hole is added starts to react, and end reaction volume is that 10 μ L, ATP concentration are 25 μM, and PIP2 concentration is 50 μM, and PI3K alpha kinase concentration is 1.65nM.Plate is covered and will be reacted and is carried out 1 hour in room temperature, the kinases Kinase-Glo of every 10 μ L of hole is then added
TMReagent terminates reaction.Plate is incubated for 15 minutes, then reads cold light in 2104 multiple labeling micropore board detector plate reader of EnVision.
Percentage is inhibited to calculate based on following formula:
Inhibit %=100- (max-sample RLU)/(max-min) * 100.
Wherein sample RLU is the cold light reading under given compound concentration, and min refers to that the reading of DMSO control, max refer to the reading of no enzyme activity control.By using the IC for calculating compound in Excel in XLfit program
50, the results are shown in Table 1.
Table 1:PI3K alpha kinase inhibitory activity
| Embodiment | PI3KαIC 50(nM) |
| 1 | 0.80 |
| 2 | 0.72 |
| 3 | 1.1 |
| 4 | 0.74 |
| 5 | 2.7 |
| 6 | 2.3 |
| 7 | 1.1 |
| 8 | 1.0 |
| 9 | 0.86 |
| 10 | 3.8 |
| 11 | 0.94 |
| 12 | 4.5 |
| 13 | 0.84 |
| 14 | 3.3 |
| 15 | 5.5 |
| 16 | 4.1 |
| 17 | 2.3 |
| 18-1 | 1.1 |
| 18-2 | 0.8 |
| 19 | 1.0 |
| 20 | 1.3 |
| 21 | 1.0 |
| 22 | 0.6 |
| 23 | 1.1 |
| 24 | 0.8 |
| 25 | 1.6 |
| 26 | 0.79 |
| 27 | 1.7 |
| 28 | 1.2 |
| 29 | 1.1 |
| 30 | 1.3 |
| 31 | 3.8 |
| 32 | 0.82 |
| 33 | 1.7 |
| 34 | 1.6 |
| 35 | 1.8 |
| 36 | 2.2 |
| 37 | 2.3 |
| 38 | 2.3 |
| 39 | 15 |
| 40 | 8.5 |
| 41 | 5.0 |
| 42 | 1.1 |
| 43 | 10 |
| 44 | 0.65 |
| 45 | 0.92 |
| 46 | 0.70 |
| 47 | 1.4 |
| 48 | 2.1 |
| 49 | 0.76 |
| 50 | 2.2 |
| 51 | 0.72 |
| 52 | 2.1 |
| 53 | 0.73 |
| 54 | 1.6 |
| 55 | 1.7 |
| 56 | 0.92 |
| 57 | 1.7 |
| 58 | 1.0 |
| 59 | 0.74 |
| 60 | 1.3 |
| 61 | 1.0 |
| 62 | 2.5 |
| 63 | 10 |
| 64 | 1.5 |
| 65 | 2.7 |
| 66 | 1.7 |
| 67 | 6.1 |
| 68 | 1.6 |
| 69 | 2.2 |
| 70 | 0.90 |
| 71 | 1.9 |
| 72 | 0.70 |
| 73 | 1.3 |
| 74 | 1.1 |
The survival rate of experimental example 2:MTT method measurement tumour cell
After the human lung carcinoma cell NCI-H460 of logarithmic growth phase is digested with 0.25% pancreas enzyme -EDTA, it is configured to certain density single cell suspension, 96 orifice plates are inoculated in by 1200/hole, 100 μ L are added in every hole, after for 24 hours, the untested compound of various concentration is added and the fresh culture of coordinative solvent control, every hole add 100 μ L (DMSO final concentration < 0.2%), every kind of test-compound sets 6-9 concentration group, and every group sets three parallel holes.In 5%CO
2, continue to cultivate 96h at 37 DEG C, the PBS solution of the MTT containing 5mg/mL of 20 μ L Fresh is added in every hole, continue after cultivating 4h, abandon supernatant, 150 μ L DMSO dissolution MTT first hairpin precipitating is added in every hole, after microoscillator concussion mixes, OD value (optical density is measured under the conditions of wavelength 570nm, OD), and the tumour cell handled using DMSO solvent is control group, untested compound is calculated to the inhibiting rate of growth of tumour cell with following equation, and IC is calculated by SPSS16.0
50:
Inhibiting rate (%)=(OD
Control- OD
Compound)/OD
Control× 100%
Wherein, OD
ControlFor the mean OD value of control group, OD
ControlTo give the mean OD value under compound concentration.
It the results are shown in Table 2.
Table 2: to the antiproliferative activity of human lung carcinoma cell NCI-H460
| Embodiment | H460IC 50(μM) |
| 1 | 0.029 |
| 2 | 0.017 |
| 3 | 0.096 |
| 4 | 0.025 |
| 5 | 0.86 |
| 6 | 0.93 |
| 7 | 2.1 |
| 8 | 1.2 |
| 9 | 0.093 |
| 10 | 2.2 |
| 11 | 0.094 |
| 12 | 2.3 |
| 13 | 0.021 |
| 14 | 2.0 |
| 15 | 0.66 |
| 16 | 1.1 |
| 17 | 0.083 |
| 18-1 | 0.030 |
| 18-2 | 0.057 |
| 19 | 0.041 |
| 20 | 0.24 |
| 21 | 0.063 |
| 22 | 0.096 |
| 23 | 0.094 |
| 24 | 0.063 |
| 25 | 0.20 |
| 26 | 0.14 |
| 27 | 0.20 |
| 28 | 0.28 |
| 29 | 0.059 |
| 30 | 0.24 |
| 31 | 0.41 |
| 32 | 0.10 |
| 33 | 0.10 |
| 34 | 0.11 |
| 35 | 0.10 |
| 36 | 0.40 |
| 37 | 0.25 |
| 38 | 0.31 |
| 39 | 1.7 |
| 40 | 2.0 |
| 41 | 1.4 |
| 42 | 0.53 |
| 43 | 4.0 |
| 44 | 0.029 |
| 45 | 0.045 |
| 46 | 0.029 |
| 47 | 0.57 |
| 48 | 0.28 |
| 49 | 0.034 |
| 50 | 0.79 |
| 51 | 0.032 |
| 52 | 0.67 |
| 53 | 0.038 |
| 54 | 0.40 |
| 55 | 0.097 |
| 56 | 0.073 |
| 57 | 0.45 |
| 58 | 0.056 |
| 59 | 0.017 |
| 60 | 0.24 |
| 61 | 0.045 |
| 62 | 0.26 |
| 63 | 2.1 |
| 64 | 0.39 |
| 65 | 0.63 |
| 66 | 0.23 |
| 67 | 3.5 |
| 68 | 0.34 |
| 69 | 0.050 |
| 70 | 0.022 |
| 71 | 1.0 |
| 72 | 0.50 |
| 73 | 0.74 |
| 74 | 0.87 |
Experimental example 3: nude mouse xenograft efficacy study
Human lung cancer NCI-H460 tumour cell is collected under aseptic condition, adjusts cell density to 1 × 10 with sterile saline
6A/ml takes 0.2ml to be inoculated in nude mice armpit dorsal sc, to tumour growth to diameter 1cm size, takes out under aseptic condition, is cut into the tumor mass of 1mm × 1mm size, be uniformly inoculated in nude mice armpit dorsal sc.To tumour growth to 100~300mm after 6 days
3Afterwards, animal is grouped at random, starts that (being denoted as the 1st day) is administered.Untested compound is administered orally daily.It weighs in twice a week and is removed tumor tissues by nude mice dislocation execution after administration 16 days with the length and width of vernier caliper measurement tumour, weigh and take pictures.Tumor control rate is finally calculated, antitumor action intensity is evaluated with tumor control rate, the results are shown in Table 3, table 4, Fig. 1 and Fig. 2.
Gross tumor volume is calculated according to following formula:
Gross tumor volume=(a × b
2)/2, a and b respectively indicates knurl length and width.
Tumor growth inhibition percentage is calculated according to following formula:
Tumor growth inhibition (%)=(1-T/C) × 100, T is the final gross tumor volume of untested compound group, and C is the final gross tumor volume of solvent control group.
3. embodiment 9 of table to human lung cancer NCI-H460 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect
4. embodiment 44 of table to human lung cancer NCI-H460 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect
Human gastric cancer HGC-27 tumour cell is collected under aseptic condition, adjusts cell density to 1 × 10 with sterile saline
6A/mL takes 0.2mL to be inoculated in nude mice armpit dorsal sc, to tumour growth to diameter 1cm size, takes out under aseptic condition, is cut into the tumor mass of 1mm × 1mm size, be uniformly inoculated in nude mice armpit dorsal sc.After two weeks to tumour growth to 100~300mm
3Afterwards, animal is grouped at random, starts that (being denoted as the 0th day) is administered.Untested compound is administered orally daily.It weighs in twice a week and is removed tumor tissues by nude mice dislocation execution after administration 20 days with the length and width of vernier caliper measurement tumour, weigh and take pictures.Tumor control rate is finally calculated, antitumor action intensity is evaluated with tumor control rate, the results are shown in Table 5 and Fig. 3.
Gross tumor volume is calculated according to following formula:
Gross tumor volume=(a × b
2)/2, a and b respectively indicates knurl length and width.
Tumor growth inhibition percentage is calculated according to following formula: Tumor growth inhibition (%)=(1-T/C) × 100, T is untested compound group gross tumor volume, and C is solvent control group gross tumor volume.
Tumour regression percentage is calculated according to following formula: 100 × (final gross tumor volume-primary tumor volume)/primary tumor volumes.
5. embodiment 32 of table to human gastric cancer HGC-27 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect
Pharmacological activity is summarized:
All embodiments all show strong inhibitory activity, IC to PI3K alpha kinase
50Value is respectively less than 11nM.All embodiments all show strong antiproliferative activity, IC to human lung carcinoma cell NCI-H460
50Value is respectively less than 5 μM.Wherein, embodiment 9 and 44 pair human lung cancer NCI-H460 has significant inhibiting effect in the growth of nude mice by subcutaneous heteroplastic transplantation tumor；Embodiment 32 has significant inhibiting effect in the growth of nude mice by subcutaneous heteroplastic transplantation tumor to human gastric cancer HGC-27.
Claims (35)
- A kind of formula (I) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt:WhereinR 1For C 1-3Alkyl；L is selected from a singly-bound or C 1-3Alkylidene, wherein the C 1-3Alkylidene is optionally replaced by one or more Ra；Ra is selected from hydrogen, halogen or C 1-3Alkyl；R 2Selected from hydrogen, C 1-3Alkyl, C 1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；As the R 2When not being hydrogen, optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino；R 3Selected from C 1-3Alkoxy, halogen or C 1-3Alkyl；R 4Selected from C 1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C 1-3Alkyl, amino, C 1-3Alkyl amino, two (C 1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy；R 5Selected from hydrogen, amino, C 1-3Alkyl amino, C 1-3Alkyl-carbonyl-amino or cyclopropyl methylamino.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, which is characterized in that shown in the compound such as formula (II):WhereinL is selected from a singly-bound or C 1-3Alkylidene, wherein the C 1-3Alkylidene is optionally replaced by one or more Ra；Ra is selected from hydrogen, halogen or C 1-3Alkyl；R 1Selected from hydrogen, C 1-3Alkyl, C 1-3Alkoxy, 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；As the R 1When not being hydrogen, optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino；R 2Selected from C 1-3Alkoxy, halogen or C 1-3Alkyl；R 3Selected from C 1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl replace: hydrogen, halogen, C wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally independently selected by one or more from group below 1-3Alkyl, amino, C 1-3Alkyl amino, two (C 1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 2, which is characterized in that the R 1Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；R 1Optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 2, which is characterized in that the R 1For 3-7 member oxygen heterocycle alkyl, R 1Optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 4, wherein R 1It is selected from:M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to any one of claims 2 to 5, which is characterized in that each Rb is independently selected from F, methyl or methoxy.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to any one of claims 2 to 5, wherein L is selected from singly-bound or-CH 2-。
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to any one of claims 2 to 5, wherein R 2Selected from methoxyl group, chlorine or methyl.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to any one of claims 2 to 5, wherein R 3Selected from C 1-3Alkyl, 3-7 member naphthenic base, phenyl or thienyl replace: hydrogen, halogen, C wherein the phenyl and thienyl are optionally independently selected by one or more from group below 1-3Alkyl, amino, C 1-3Alkyl amino, two (C 1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 9, wherein R 3Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally independently selected by one or more from fluorine or the group of chlorine replaces.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 2, wherein the compound is selected from:
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, which is characterized in that shown in the compound such as formula (III):WhereinR 1Selected from C 1-3Alkyl, C 1-3Alkyl-carbonyl or Cvclopropvlmethvl；L is selected from a singly-bound or C 1-3Alkylidene, wherein the C 1-3Alkylidene is optionally replaced by one or more Ra；Ra is selected from hydrogen, halogen or C 1-3Alkyl；R 2Selected from C 1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl or 5-6 unit's heteroaryl are optionally replaced by least one group selected from the following: halogen, C 1-3Alkyl, amino, C 1-3Alkyl amine group, two (C 1-3Alkyl) amido, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy；Ring A is selected from 3-7 member naphthenic base or 3-7 membered heterocycloalkyl；Each R 3Independently selected from hydrogen, C 1-3Alkyl, halogen, cyano, trifluoromethyl, C 1-3The C that alkoxy, hydroxyl replace 1-3Alkyl, C 1-3Alkyl amine group or two (C 1-3Alkyl) amido；M is 0,1,2,3 or 4.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 12, which is characterized in that the ring A is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；Each R 3Independently selected from hydrogen, C 1-3Alkyl, halogen, cyano, trifluoromethyl, C 1-3The C that alkoxy, hydroxyl replace 1-3Alkyl, C 1-3Alkyl amine group or two (C 1-3Alkyl) amido；M is 0,1,2,3 or 4.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 12, which is characterized in that the ring A is 3-7 member oxygen heterocycle alkyl；Each R 3Independently selected from hydrogen, C 1-3Alkyl, halogen, cyano, trifluoromethyl, C 1-3The C that alkoxy, hydroxyl replace 1-3Alkyl, C 1-3Alkyl amine group or two (C 1-3Alkyl) amido；M is 0,1,2,3 or 4.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 14, which is characterized in that the ring A is selected from:Each R 3Independently selected from hydrogen, C 1-3Alkyl, halogen, cyano, trifluoromethyl, C 1-3The C that alkoxy, hydroxyl replace 1-3Alkyl, C 1-3Alkyl amine group or two (C 1-3Alkyl) amido；M is 0,1,2,3 or 4.
- 2 to 15 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, which is characterized in that each R 3Independently selected from methyl.
- According to claim 1,2 to 15 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein L is selected from singly-bound or-CH 2-。
- 2 to 15 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R 1Selected from methyl, ethyl, Cvclopropvlmethvl or acetyl group.
- 2 to 15 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R 2Selected from C 1-3Alkyl, 3-7 member naphthenic base, phenyl or thienyl replace: hydrogen, halogen, C wherein the phenyl and thienyl are optionally independently selected by one or more from group below 1-3Alkyl, amino, C 1-3Alkyl amino, two (C 1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 19, wherein R 2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally independently selected by one or more from fluorine or the group of chlorine replaces.
- 2 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from:
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 1, which is characterized in that shown in the compound such as formula (IV):WhereinR 1For C 1-3Alkyl；L is selected from a singly-bound or C 1-3Alkylidene, wherein the C 1-3Alkylidene is optionally replaced by one or more Ra；Ra is selected from hydrogen, halogen or C 1-3Alkyl；R 2Selected from hydrogen, C 1-3Alkyl, C 1-3Alkoxy, 3-7 member naphthenic base, 3-7 membered heterocycloalkyl or 5-6 unit's heteroaryl；As the R 2When not being hydrogen, optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino；R 3Selected from C 1-3Alkoxy, halogen or C 1-3Alkyl；R 4Selected from C 1-3Alkyl, 3-7 member naphthenic base, 6-10 member aryl or 5-6 unit's heteroaryl, wherein the 6-10 member aryl and 5-6 unit's heteroaryl are optionally replaced by one or more selected from following group: hydrogen, halogen, C 1-3Alkyl, amino, C 1-3Alkyl amino, two (C 1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 22, which is characterized in that the R 2Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；R 2Optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 22, which is characterized in that the R 2For 3-7 member oxygen heterocycle alkyl, R 2Optionally replaced by m Rb；M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 24, wherein R 2It is selected from:M is 0,1,2,3 or 4；Each Rb is independently selected from halogen, cyano, hydroxyl, trifluoromethyl, C 1-3Alkyl, C 1-3Alkoxy, C 1-3Hydroxy alkyl, C 1-3Alkyl amino or two (C 1-3Alkyl) amino.
- According to the described in any item compounds of claim 22 to 25, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, which is characterized in that the Rb is independently selected from F or methyl.
- According to the described in any item compounds of claim 22 to 25, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein L is selected from singly-bound or-CH 2-。
- According to the described in any item compounds of claim 22 to 25, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein R 3Selected from methoxyl group, chlorine or methyl.
- According to the described in any item compounds of claim 22 to 25, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein R 4Selected from C 1-3Alkyl, 3-7 member naphthenic base, phenyl or thienyl replace: hydrogen, halogen, C wherein the phenyl and thienyl are optionally independently selected by one or more from group below 1-3Alkyl, amino, C 1-3Alkyl amino, two (C 1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C 1-3Alkoxy.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 29, wherein R 4Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally independently selected by one or more from fluorine or the group of chlorine replaces.
- Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to claim 22, wherein compound is selected from:
- A kind of pharmaceutical composition, it is characterized in that, the pharmaceutical composition includes at least one according to claim 1 to 31 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt and optional pharmaceutically acceptable carrier and/or excipient.
- Pharmaceutical composition according to claim 32, which is characterized in that the pharmaceutical composition also includes the active pharmaceutical ingredient in addition to the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt.
- Application into 31 described in any item compounds, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the drug of the disease according to the described in any item pharmaceutical compositions of claim 32 or 33 in preparation for preventing and/or treating PI3K mediation according to claim 1.
- According to the application of claim 34, which is characterized in that the disease that the PI3K is mediated includes cancer, immunity disease, cardiovascular disease, virus infection, inflammation, metabolism/endocrine dysfunction or neurological disease.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016112141029 | 2016-12-26 | ||
| CN201611211589.5A CN108239075B (en) | 2016-12-26 | 2016-12-26 | Quinazoline compound, preparation method, application and pharmaceutical composition thereof |
| CN2016112115895 | 2016-12-26 | ||
| CN201611204309.8A CN108239074B (en) | 2016-12-26 | 2016-12-26 | Quinazoline compound, preparation method, application and pharmaceutical composition thereof |
| CN2016112043098 | 2016-12-26 | ||
| CN201611214102.9A CN108239076B (en) | 2016-12-26 | 2016-12-26 | Quinazoline compound, preparation method, application and pharmaceutical composition thereof |
| PCT/CN2017/118771 WO2018121550A1 (en) | 2016-12-26 | 2017-12-26 | Quinazoline compound and preparation method, application, and pharmaceutical compostion thereof |
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| CN110382490A true CN110382490A (en) | 2019-10-25 |
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| US (3) | US11534443B2 (en) |
| EP (3) | EP3560921A4 (en) |
| JP (3) | JP7077323B2 (en) |
| CN (1) | CN110382490A (en) |
| AU (3) | AU2017389818B2 (en) |
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| WO (1) | WO2018121550A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114555588A (en) * | 2019-11-07 | 2022-05-27 | 南京正大天晴制药有限公司 | Quinazolines as AXL inhibitors |
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| AU2017389818B2 (en) | 2016-12-26 | 2022-04-07 | Institute Of Materia Medica, Chinese Academy Of Medical Sciences | Quinazoline compound and preparation method, application, and pharmaceutical compostion thereof |
| CN113620976B (en) * | 2020-05-09 | 2023-09-26 | 中国医学科学院药物研究所 | Thiazolopyrimidine compound, preparation method, application and pharmaceutical composition thereof |
| WO2022109001A1 (en) | 2020-11-18 | 2022-05-27 | Deciphera Pharmaceuticals, Llc | Gcn2 and perk kinase inhibitors and methods of use thereof |
| US20240148895A1 (en) * | 2022-08-26 | 2024-05-09 | Eisai R&D Management Co., Ltd. | Antibody-drug conjugate |
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| CN108239074A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition |
| CN108239076A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition |
| CN108239075A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition |
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| EP2211615A4 (en) | 2007-10-22 | 2010-10-13 | Glaxosmithkline Llc | Pyridosulfonamide derivatives as pi3 kinase inhibitors |
| AU2014250836C1 (en) * | 2013-04-12 | 2019-01-17 | Asana Biosciences, Llc | Quinazolines and azaquinazolines as dual inhibitors of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways |
| AU2017389818B2 (en) | 2016-12-26 | 2022-04-07 | Institute Of Materia Medica, Chinese Academy Of Medical Sciences | Quinazoline compound and preparation method, application, and pharmaceutical compostion thereof |
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- 2017-12-26 EP EP17886474.0A patent/EP3560921A4/en active Pending
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| WO2008157191A2 (en) * | 2007-06-14 | 2008-12-24 | Smithkline Beecham Corporation | Quinazoline derivatives as pi3 kinase inhibitors |
| CN108239074A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition |
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| AU2017389818B2 (en) | 2022-04-07 |
| EP3560921A1 (en) | 2019-10-30 |
| US11534443B2 (en) | 2022-12-27 |
| EP4169918A1 (en) | 2023-04-26 |
| CA3048546A1 (en) | 2018-07-05 |
| EP3560921A4 (en) | 2020-07-29 |
| JP2022119852A (en) | 2022-08-17 |
| JP7384535B2 (en) | 2023-11-21 |
| WO2018121550A1 (en) | 2018-07-05 |
| AU2022202885B2 (en) | 2022-10-13 |
| AU2022202885A1 (en) | 2022-05-26 |
| JP2022119853A (en) | 2022-08-17 |
| CA3174890A1 (en) | 2018-07-05 |
| US20230113478A1 (en) | 2023-04-13 |
| EP4169917A1 (en) | 2023-04-26 |
| AU2022202886B2 (en) | 2023-04-13 |
| JP7384536B2 (en) | 2023-11-21 |
| JP2020503321A (en) | 2020-01-30 |
| US20210128559A1 (en) | 2021-05-06 |
| US20230110550A1 (en) | 2023-04-13 |
| AU2022202886A1 (en) | 2022-05-26 |
| JP7077323B2 (en) | 2022-05-30 |
| CA3174865A1 (en) | 2018-07-05 |
| AU2017389818A1 (en) | 2019-08-08 |
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